Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases

ABSTRACT

The present disclosure provides non-naturally occurring polyphenol compounds that upregulate the expression of Apolipoprotein A-I (ApoA-I). The disclosed compositions and methods can be used for treatment and prevention of cardiovascular disease and related disease states, including cholesterol or lipid related disorders, such as, e.g., atherosclerosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This divisional application claims priority to U.S. patent applicationSer. No. 11/255,103, filed Oct. 20, 2005, which claims the benefit ofpriority to U.S. provisional application 60/620,888, filed Oct. 20,2004; U.S. provisional application 60/626,819, filed Nov. 10, 2004; andU.S. provisional application 60/665,859, filed Mar. 29, 2005, all ofwhich are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present disclosure relates to polyphenol compounds, which are usefulfor regulating the expression of apolipoprotein A-I (ApoA-I), and theiruse for treatment and prevention of cardiovascular disease and relateddisease states, including cholesterol or lipid related disorders, suchas, e.g., atherosclerosis.

BACKGROUND

Epidemiologic data demonstrate an inverse relationship betweencirculating levels of high density lipoprotein cholesterol (HDL-C) andthe incidence of clinically significant atherosclerosis. Each 1 mg/dlincrement in the HDL-C serum level is associated with a 2-3% decrementin cardiovascular risk; a 1% reduction in LDL-C reduces coronary heartdisease (CHD) risk by 2%. Gordon et al., Am. J. Med. 62(5):707-14(1997). Experimental evidence further supports the protective effect ofHDL against cardiovascular disease. For example, in subjects with lowHDL-C, administration of gemfibrozil results in a 6% increase in theHDL-C level and a corresponding 22% reduction of the CHD risk. Rubins etal., N. Engl. J. Med. 341(6):410-8 (1999). Observations in geneticdisorders associated with low HDL due to reduced ApoA-I expression, alsoindicate the link between elevated risk of CHD and low HDL-C.

HDL appears to exert its antiatherogenic effect by mediating reversecholesterol transport (RCT), in which cholesterol is recruited fromperipheral tissues and transported to the liver. In addition, HDL alsoexerts anti-inflammatory, antioxidant effects and promotes fibrinolysis.HDL particles protect against oxidation of LDL, an important initialstep in promoting cholesterol uptake by arterial macrophages. HDL existsin two main forms, one containing both apolipoprotein A-I (ApoA-I) andapolipoprotein A-II (ApoA-II), and the other containing ApoA-I withoutApoA-II. Schultz et al., Nature 365(6448):762-4 (1993). Thecardioprotective effect of HDL is mostly, but not exclusively,attributable to ApoA-I.

Clinical and experimental data suggest that the production of ApoA-I isa critical determinant of circulating HDL. For example, persons withfamilial hyperalphalipoproteinemia (elevated ApoA-I) appear to beprotected from atherosclerosis, while those deficient in ApoA-I(hypoalphalipoproteinemia) show accelerated cardiovascular disease. Inaddition, various experimental manipulations to increase production ofApoA-I are associated with reduced atherogenicity. For example, humanApoA-I is protective in transgenic animal models (Shah et al.,Circulation 97(8):780-5 (1998; Rubin et al., Nature 353(6341):265-7(1991), and treatment with ApoA-I_(Milano) prevents atheroscleroticlesions and leads to regression of atherosclerotic plaques in humanpatients (Nissen et al., JAMA 290(17):2292-300 (2003)). Further lines ofresearch supporting an antiatherogenic role of ApoA-I includeenhancement of reverse cholesterol transport, attenuation of oxidativestress, increased peroxonase activity, enhanced anticoagulant activity,and anti-inflammatory activity. Accordingly, ApoA-I is an attractivetarget for therapeutic intervention.

Currently available therapeutic agents that increase the plasmaconcentration of ApoA-I, for example, recombinant ApoA-I or peptidesthat mimic ApoA-I, have potential drawbacks related to manufacturing andreproducibility, e.g., stability during storage, delivery of an activeproduct, and in vivo half-life. Therefore, small molecule compounds thatupregulate the production of endogenous ApoA-I, such as, e.g.,transcriptional upregulators of ApoA-I expression, are very attractiveas new therapeutic agents for cardiovascular disease.

One class of compounds that are thought to contribute to the preventionof various diseases, including cancer and cardiovascular diseases, ispolyphenols. Polyphenols are common constituents of the human diet,present in most food and beverages of plant origin, and are the mostabundant dietary antioxidants. However, polyphenols protectiveproperties are often minimized due to poor bioavailability, lack ofclinical significance, and deleterious effects at high concentrations.For example, the most abundant and available source of resveratrol forconsumers, red wine, cannot be consumed in therapeutically efficaciousquantities on a daily basis due to the numerous well documenteddeleterious effects of excessive alcohol consumption. The actions ofresveratrol may be better or safer in the absence of alcohol.

Several human clinical studies, involving foods or beverages, have yetto demonstrate an unequivocal benefit on primary clinical endpoints,such as oxidative stress, lipemia, and inflammation. For example, out of12 recent intervention studies with differing polyphenol sources, 6showed no effect on lipid parameters and the other 6 showed animprovement in the lipid parameters. Manach, Curr. Opin. Lipidol.16(1):77-84 (2005). Such contradictory data has limited the potentialuse of polyphenols, despite their many beneficial properties.

The use of naturally occurring polyphenols as a potential therapy hasalso been impeded by the inability to achieve efficacious levels ofbioavailability. The bioavailability of polyphenols in humans range from1% to 26% and has a large inter-individual variability as well asvariability between different polyphenols. Polyphenols differ in howthey are absorbed, metabolized, and excreted. For example, polyphenolflavonoids, such as quercetin, have been reported to have less than 1%intestinal absorption following oral administration. Gugler et al., Eur.J. Clin. Pharm. 9:223 (1975). In addition, metabolites are known tonegatively influence the biological activity of the parent compounds.Such metabolites often differ from the parent compound in terms oftoxicity, efficacy, and length of residence in the plasma. Anotherlimiting factor may be polyphenols' poor solubility in water whichlimits the routes of administration. These and other factors have madeit difficult to determine appropriate dosages of the naturally occurringpolyphenols, naringenin or resveratrol, for use in humans.

Thus, there exists a need for synthetic polyphenols to be developed astherapeutic agents for the treatment and prevention of cardiovascularand related diseases, particularly, cholesterol or lipid relateddisorders, such as, e.g., atherosclerosis. It is therefore one of theobjects of the present invention to provide compounds that upregulatethe expression of ApoA-I, while having more favorable pharmacologicalproperties than naturally occurring polyphenols.

SUMMARY

The methods of invention include administering to a mammal (e.g., ahuman) in need thereof a therapeutically effective amount of a flavanoidcompound of Formula I:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂,wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ areeach independently selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or 6-membered ringto form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then pis 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond;

wherein if Y is O, then X is not CO;

wherein if X is O, the Z₁ is a single bond;

wherein if X is O and Z₂ is a single bond, then R₁₀ is not hydroxyl orester;

and pharmaceutically acceptable salts and hydrates thereof.

Methods of invention also include administering to a mammal (e.g., ahuman) in need thereof a therapeutically effective amount of anisoflavanoid compound of Formula IV:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂,wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈are each independently selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₈ are connected in a 5 or 6-memberedring to form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then pis 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond;

wherein if Y is O, then X is not CO;

wherein if X is O, Y is CO and Z₂ is a double bond, then at least one ofR₅, R₆, R₈ and R₉ is not hydrogen;

and pharmaceutically acceptable salts and hydrates thereof.

In certain embodiments, the methods and compositions of the inventionare useful for treatment of diseases characterized by reduced ApoA-Iand/or HDL. The compounds and compositions of the invention can be usedto increase expression of ApoA-I. Increasing expression of ApoA-I refersto transcriptionally modulating the expression of the ApoA-I genethereby affecting the level of the ApoA-I protein expressed, i.e.,synthesized and secreted, by the cell. An increase in ApoA-I proteinexpression leads to an increase in blood levels of HDL. Thus, themethods and compounds of the invention may further be used to reduceplasma cholesterol levels. Accordingly, the methods and compositions ofthe invention can be used for treatment and prevention of cardiovasculardisease and related disease states, particularly, cholesterol or lipidrelated disorders, such as, atherosclerosis, dyslipidemias,dyslipoproteinemias, hypertension, coronary artery disease,cerebrovascular disease, and the like.

In one aspect, the invention provides a method for prevention ofarteriosclerosis lesion development in a mammal, including thedevelopment of new arteriosclerotic lesions. In another aspect, thepresent invention provides a method regressing arteriosclerosis lesions.

The methods and compounds of the invention may further be used to lowerblood levels of LDL and triglycerides and/or to increase free radicalscavenging. In addition, these methods and compositions may also be usedto inhibit HMG-CoA reductase, inhibit ACAT, and/or increase ABCA-Iactivity.

In a further aspect, the invention provides methods and compositions foreffecting an increase of HDL in a mammal comprising, wherein thecompound is a flavonoid or a isoflavonoid, each derivatized withcovalently bonded niacin. In certain embodiments, the covalent bondcomprises a reverse ester linkage.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows results from an ELISA analysis to measure ApoA-I proteincontent of conditioned media from: (1) untreated HepG2 cells: (2) HepG2cells treated with solvent: and (3) HepG2 cells treated with testcompound, at 0, 6, and 24 hours after exposure.

FIG. 2 shows permeability of Caco-2 cells to 4′-hydroxyflavone,2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one, and2-(2-amino-4-hydroxy-phenyl)-chromen-4-one over time (expressed aspercent transported Paap (cm/s)).

FIG. 3(A) shows the effect of 4′-hydroxyflavone, and4-(4-oxo4H-chromen-2-yl)phenyl nicotinate on ApoA-I levels in hApoA-Itransgenic mice (expressed as net percent change in ApoA-I). FIG. 3(B)shows the change in HDL-C, large HDL (HDL2), small HDL (HDL3) and totalcholesterol (TC) levels in hApoA-I transgenic mice followingadministration of 4′-hydroxyflavone. FIG. 3(C) graphically depicts thechange in liver weight in hApoA-I transgenic mice followingadministration of 4′-hydroxyflavone, 4-(4-oxo4H-chromen-2-yl)phenylnicotinate, and fenofibrate.

DETAILED DESCRIPTION Definitions

The term “aldehyde” or “formyl” as used herein refers to the radical—CHO.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms,referred to herein as (C₂-C₂₂)alkenyl, (C₂-C₈)alkenyl, and(C₂-C₆)alkenyl, respectively. Exemplary alkenyl groups include, but arenot limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl, etc.

The term “alkoxy” as used herein refers to an alkyl group attached to anoxygen (—O-alkyl-). “Alkoxy” groups also include an alkenyl groupattached to an oxygen (“alkenoxy”) or an alkynyl group attached to anoxygen (“alkynoxy”) groups. Exemplary alkoxy groups include, but are notlimited to, groups with an alkyl, alkenyl or alkynyl group of 1-22, 1-8,or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkoxy,(C₁-C₈)alkoxy, and (C₁-C₆)alkoxy, respectively. Exemplary alkoxy groupsinclude, but are not limited to methoxy, ethoxy, etc.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-22, 1-8,or 1-6 carbon atoms, referred to herein as (C₁-C₂₂)alkyl, (C₁-C₈)alkyl,and (C₁-C₆)alkyl, respectively. Exemplary alkyl groups include, but arenot limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl,hexyl, heptyl, octyl, etc.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-22, 2-8, or 2-6 carbon atoms,referred to herein as (C₂-C₂₂)alkynyl, (C₂-C₈)alkynyl, and(C₂-C₆)alkynyl, respectively. Exemplary alkynyl groups include, but arenot limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl, etc.

The term “amide” as used herein refers to a radical of the form—R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, or —C(O)NR_(b)R_(c),wherein R_(b) and R_(c) are each independently selected from alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro,phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide andthioketone. The amide can be attached to another group through thecarbon, the nitrogen, R_(b), R_(c), or R_(a). The amide also may becyclic, for example R_(b) and R_(c), R_(a) and R_(b), or R_(a) and R_(c)may be joined to form a 3- to 12-membered ring, such as a 3- to10-membered ring or a 5- to 6-membered ring. The term “amide”encompasses groups such as sulfonamide, urea, carbamate, carbamic acid,and cyclic versions thereof. The term “amide” also encompasses an amidegroup attached to a carboxy group, e.g., -amide-COOH or salts such as-amide-COONa, etc, an amino group attached to a carboxy group, e.g.,-amino-COOH or salts such as -amino-COONa, etc.

The term “amine” or “amino” as used herein refers to a radical of theform —NR_(d)R_(e), —N(R_(d))R_(e)—, or —R_(e)N(R_(d))R_(f) where R_(d),R_(e), and R_(f) are independently selected from alkoxy, aryloxy, alkyl,alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy,cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. The aminocan be attached to the parent molecular group through the nitrogen,R_(d), R_(e) or R_(f). The amino also may be cyclic, for example any twoof R_(a), R_(b), and R_(c) may be joined together or with the N to forma 3- to 12-membered ring, e.g., morpholino or piperidinyl. The termamino also includes the corresponding quaternary ammonium salt of anyamino group, e.g., —[N(R_(d))(R_(e))(R_(f))]⁺. Exemplary amino groupsinclude aminoalkyl groups, wherein at least one of R_(d), R_(e), orR_(f) is an alkyl group.

The term “aryl” as used herein refers to a mono-, bi-, or othermulti-carbocyclic, aromatic ring system. The aryl group can optionallybe fused to one or more rings selected from aryls, cycloalkyls, andheterocyclyls. The aryl groups of this invention can be substituted withgroups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone. Exemplary aryl groups include, but are notlimited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl,and naphthyl, as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but arenot limited to a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryl.”

The term “arylalkyl” as used herein refers to an aryl group having atleast one alkyl substituent, e.g. -aryl-alkyl-. Exemplary arylalkylgroups include, but are not limited to, arylalkyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylalkyl.”

The term “aryloxy” as used herein refers to an aryl group attached to anoxygen atom. Exemplary aryloxy groups include, but are not limited to,aryloxys having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)aryloxy.”

The term “arylthio” as used herein refers to an aryl group attached toan sulfur atom. Exemplary arylthio groups include, but are not limitedto, arylthios having a monocyclic aromatic ring system, wherein the ringcomprises 6 carbon atoms, referred to herein as “(C₆)arylthio.”

The term “arylsulfonyl” as used herein refers to an aryl group attachedto a sulfonyl group, e.g., —S(O)₂-aryl-. Exemplary arylsulfonyl groupsinclude, but are not limited to, arylsulfonyls having a monocyclicaromatic ring system, wherein the ring comprises 6 carbon atoms,referred to herein as “(C₆)arylsulfonyl.”

The term “benzyl” as used herein refers to the group —CH₂-phenyl.

The term “bicyclic aryl” as used herein refers to an aryl group fused toanother aromatic or non-aromatic carbocylic or heterocyclic ring.Exemplary bicyclic aryl groups include, but are not limited to, naphthylor partly reduced forms thereof, such as di-, tetra-, orhexahydronaphthyl.

The term “bicyclic heteroaryl” as used herein refers to a heteroarylgroup fused to another aromatic or non-aromatic carbocylic orheterocyclic ring. Exemplary bicyclic heteroaryls include, but are notlimited to, 5,6 or 6,6-fused systems wherein one or both rings containheteroatoms. The term “bicyclic heteroaryl” also encompasses reduced orpartly reduced forms of fused aromatic system wherein one or both ringscontain ring heteroatoms. The ring system may contain up to threeheteroatoms, independently selected from oxygen, nitrogen, or sulfur.The bicyclic system may be optionally substituted with one or moregroups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone. Exemplary bicyclic heteroaryl's include, butare not limited to, quinazolinyl, benzothiophenyl, benzoxazolyl,benzimidazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl,isoquinolinyl, phthalazinyl, benzotriazolyl, benzopyridinyl, andbenzofuranyl.

The term “carbamate” as used herein refers to a radical of the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro,phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide andthioketone. Exemplary carbamates include, but are not limited to,arylcarbamates or heteroaryl carbamates, e.g. wherein at least one ofR_(g), R_(h) and R_(i) are independently selected from aryl orheteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “carboxy” as used herein refers to the radical —COOH or itscorresponding salts, e.g. —COONa, etc. The term carboxy also includes“carboxycarbonyl,” e.g. a carboxy group attached to a carbonyl group,e.g., —C(O)—COOH or salts such as —C(O)—COONa, etc.

The term “cyano” as used herein refers to the radical —CN.

The term “cycloalkoxy” as used herein refers to a cycloalkyl groupattached to an oxygen.

The term “cycloalkyl” as used herein refers to a monovalent saturated orunsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of3-12 carbons, or 3-8 carbons, referred to herein as “(C₃-C₈)cycloalkyl,”derived from a cycloalkane. Exemplary cycloalkyl groups include, but arenot limited to, cyclohexanes, cyclohexenes, cyclopentanes, andcyclopentenes. Cycloalkyl groups may be substituted with alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Cycloalkyl groups can be fused to other cycloalkyl, aryl, orheterocyclyl groups.

The term “dicarboxylic acid” as used herein refers to a group containingat least two carboxylic acid groups such as saturated and unsaturatedhydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylicacids include alkyl dicarboxylic acids. Dicarboxylic acids may besubstituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include,but are not limited to succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, maleic acid, phthalic acid,aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(−)-malicacid, (+)/(−) tartaric acid, isophthalic acid, and terephthalic acid.Dicarboxylic acids further include carboxylic acid derivatives thereof,such as anhydrides, imides, hydrazides, etc., for example, succinicanhydride, succinimide, etc.

The term “ester” refers to a radical having the structure —C(O)O—,—C(O)O—R_(j)—, —R_(k)C(O)O—R_(j)—, or —R_(k)C(O)O—, where O is not boundto hydrogen, and R_(j) and R_(k) can independently be selected fromalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,cycloalkyl, ether, formyl, haloalkyl, halogen, heteroaryl, heterocyclyl,ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid andthioketone. R_(k) can be a hydrogen, but R_(j) cannot be hydrogen. Theester may be cyclic, for example the carbon atom and R_(j), the oxygenatom and R_(k), or R_(j) and R_(k) may be joined to form a 3- to12-membered ring. Exemplary esters include, but are not limited to,alkyl esters wherein at least one of Rj or Rk is alkyl, such as-alkyl-C(O)—O—, —C(O)—O-alkyl-, -alkyl-C(O)—O-alkyl-, etc. Exemplaryesters also include aryl or heteroaryl esters, e.g. wherein at least oneof Rj or Rk is a heteroaryl group such as pyridine, pyridazine,pyrimidine and pyrazine, such as a nicotinate ester. Exemplary estersalso include reverse esters having the structure —R_(k)C(O)O—, where theoxygen is bound to the parent molecular group. Exemplary reverse estersinclude succinate, D-argininate, L-argininate, L-lysinate andD-lysinate. Esters also include carboxylic acid anhydrides and acidhalides.

The term “ether” refers to a radical having the structure—R_(l)O—R_(m)—, where R_(l) and R_(m) can independently be alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, or ether. The ethercan be attached to the parent molecular group through R_(l) or R_(m).Exemplary ethers include, but are not limited to, alkoxyalkyl andalkoxyaryl groups. Ethers also includes polyethers, e.g., where one orboth of R_(l) and R_(m) are ethers.

The terms “halo” or “halogen” or “Hal” as used herein refer to F, Cl,Br, or I.

The term “haloalkyl” as used herein refers to an alkyl group substitutedwith one or more halogen atoms. “Haloalkyls” also encompass alkenyl oralkynyl groups substituted with one or more halogen atoms.

The term “heteroaryl” as used herein refers to a mono-, bi-, ormulti-cyclic, aromatic ring system containing one or more heteroatoms,for example 1 to 3 heteroatoms, such as nitrogen, oxygen, and sulfur.Heteroaryls can be substituted with one or more substituents includingalkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone.Heteroaryls can also be fused to non-aromatic rings. Illustrativeexamples of heteroaryl groups include, but are not limited to,pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl,pyrazolyl, imidazolyl, (1,2,3,)- and (1,2,4)-triazolyl, pyrazinyl,pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, furyl,phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include,but are not limited to, a monocyclic aromatic ring, wherein the ringcomprises 2 to 5 carbon atoms and 1 to 3 heteroatoms, referred to hereinas “(C₂-C₅)heteroaryl.”

The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as usedherein refer to a saturated or unsaturated 3-, 4-, 5-, 6- or 7-memberedring containing one, two, or three heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Heterocycles can be aromatic(heteroaryls) or non-aromatic. Heterocycles can be substituted with oneor more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone.

Heterocycles also include bicyclic, tricyclic, and tetracyclic groups inwhich any of the above heterocyclic rings is fused to one or two ringsindependently selected from aryls, cycloalkyls, and heterocycles.Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, cinnolinyl,dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl,dithiazolyl, furyl, homopiperidinyl, imidazolidinyl, imidazolinyl,imidazolyl, indolyl, isoquinolyl, isothiazolidinyl, isothiazolyl,isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, oxazolidinyl,oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazinyl,pyrazolyl, pyrazolinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidyl,pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, pyrrolyl, quinolinyl,quinoxaloyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, tetrazolyl, thiadiazolyl, thiazolidinyl, thiazolyl,thienyl, thiomorpholinyl, thiopyranyl, and triazolyl.

The terms “hydroxy” and “hydroxyl” as used herein refers to the radical—OH.

The term “hydroxyalkyl” as used herein refers to a hydroxy radicalattached to an alkyl group.

The term “hydroxyaryl” as used herein refers to a hydroxy radicalattached to an aryl group.

The term “ketone” as used herein refers to a radical having thestructure —C(O)—Rn (such as acetyl, —C(O)CH₃) or —R_(n)—C(O)—R_(o)—. Theketone can be attached to another group through R_(n) or R_(o). R_(n) orR_(o) can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl or aryl,or R_(n) or R_(o) can be joined to form a 3- to 12-membered ring.

The term “monoester” as used herein refers to an analogue of adicarboxylic acid wherein one of the carboxylic acids is functionalizedas an ester and the other carboxylic acid is a free carboxylic acid orsalt of a carboxylic acid. Examples of monoesters include, but are notlimited to, to monoesters of succinic acid, glutaric acid, adipic acid,suberic acid, sebacic acid, azelaic acid, oxalic and maleic acid.

The term “nitro” as used herein refers to the radical —NO₂.

The term “perfluoroalkoxy” as used herein refers to an alkoxy group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.

The term “perfluoroalkyl” as used herein refers to an alkyl group inwhich all of the hydrogen atoms have been replaced by fluorine atoms.Exemplary perfluoroalkyl groups include, but are not limited to, C₁₋₅perfluoroalkyl, such as trifluoromethyl, etc.

The term “perfluorocycloalkyl” as used herein refers to a cycloalkylgroup in which all of the hydrogen atoms have been replaced by fluorineatoms.

The term “phenyl” as used herein refers to a 6-membered carbocyclicaromatic ring. The phenyl group can also be fused to a cyclohexane orcyclopentane ring. Phenyl can be substituted with one or moresubstituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide,amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester,ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl,ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone.

The term “phosphate” as used herein refers to a radical having thestructure —OP(O)O₂—, —R_(x)OP(O)O₂—, —OP(O)O₂R_(y)—, or—R_(x)OP(O)O₂R_(y)—, wherein R_(x) and R_(y) can be alkyl, alkenyl,alkynyl, alkoxy, amide, amino, aryl, aryloxy, carboxy, cyano,cycloalkyl, ester, ether, halogen, heterocyclyl, hydrogen, hydroxy,ketone, nitro, sulfonate, sulfonyl, and thio.

The term “sulfide” as used herein refers to the radical having thestructure R_(z)S—, where R_(z) can be alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cycloalkyl,ester, ether, formyl, haloalkyl, heteroaryl, heterocyclyl, and ketone.The term “alkylsulfide” as used herein refers to an alkyl group attachedto a sulfur atom.

The term “sulfinyl” as used herein refers to a radical having thestructure —S(O)O—, —R_(p)S(O)O—, —R_(p)S(O)OR_(q)—, or —S(O)OR_(q)—,wherein R_(p) and R_(s) can be alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro,phosphate, sulfide, sulfonyl, sulfonic acid, sulfonamide and thioketone.Exemplary sulfinyl groups include, but are not limited to,alkylsulfinyls wherein at least one of R_(p) or R_(q) is alkyl, alkenylor alkynyl.

The term “sulfonamide” as used herein refers to a radical having thestructure —(R_(r))—N—S(O)₂—R_(s)— or —R_(t)(R_(r))—N—S(O)₂—R_(s), whereR_(t), R_(r), and R_(s) can be, for example, hydrogen, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, and heterocyclyl. Exemplary sulfonamidesinclude alkylsulfonamides (e.g., where R_(s) is alkyl), arylsulfonamides(e.g., where R_(s) is aryl), cycloalkyl sulfonamides (e.g., where R_(s)is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R_(s) isheterocyclyl), etc.

The term “sulfonate” as used herein refers to the radical —OSO₃ ⁻.Sulfonate includes salts such as —OSO₃Na, —OSO₃K, etc. and the acid—OSO₃H

The term “sulfonic acid” refers to the radical —SO₃H— and itscorresponding salts, e.g. —SO₃K—, —SO₃Na—.

The term “sulfonyl” as used herein refers to a radical having thestructure R_(u)SO₂—, where R_(u) can be alkyl, alkenyl, alkynyl, amino,amide, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl. The term“alkylsulfonyl” as used herein refers to an alkyl group attached to asulfonyl group. “Alkylsulfonyl” groups can optionally contain alkenyl oralkynyl groups.

The term “thioketone” refers to a radical having the structure—R_(v)—C(S)—R_(w)—. The ketone can be attached to another group throughR_(v) or R_(w). R_(v) or R_(w) can be alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl or aryl, or R_(v) or R_(w) can be joined toform a 3- to 12-membered ring.

“Alkyl,” “alkenyl,” and “alkynyl” groups, collectively referred to as“saturated and unsaturated hydrocarbons,” can be substituted with orinterrupted by at least one group selected from alkoxy, aryloxy, alkyl,alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy,cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide, thioketone, and N.

As used herein, a “suitable substituent” refers to a group that does notnullify the synthetic or pharmaceutical utility of the compounds of theinvention or the intermediates useful for preparing them. Examples ofsuitable substituents include, but are not limited to: C₁₋₂₂, C₁₋₈, andC₁₋₆ alkyl, alkenyl or alkynyl; C₁₋₆ aryl, C₂₋₅ heteroaryl; C₃₋₇cycloalkyl; C₁₋₂₂, C₁₋₈, and C₁₋₆ alkoxy; C₆ aryloxy; —CN; —OH; oxo;halo, carboxy; amino, such as —NH(C₁₋₂₂, C₁₋₈, or C₁₋₆ alkyl),—N((C₁₋₂₂, C₁₋₈, and C₁₋₆ alkyl)₂, —NH((C₆)aryl), or —N((C₆)aryl)₂;formyl; ketones, such as —CO(C₁₋₂₂, C₁₋₈, and C₁₋₆ alkyl), —CO((C₆ aryl)esters, such as —CO₂(C₁₋₂₂, C₁₋₈, and C₁₋₁₆ alkyl) and —CO₂ (C₆ aryl).One of skill in art can readily choose a suitable substituent based onthe stability and pharmacological and synthetic activity of the compoundof the invention.

The term “pharmaceutically acceptable carrier” as used herein refers toany and all solvents, dispersion media, coatings, isotonic andabsorption delaying agents, and the like, that are compatible withpharmaceutical administration. The use of such media and agents forpharmaceutically active substances is well known in the art. Thecompositions may also contain other active compounds providingsupplemental, additional, or enhanced therapeutic functions.

The term “pharmaceutically acceptable composition” as used herein refersto a composition comprising at least one compound as disclosed hereinformulated together with one or more pharmaceutically acceptablecarriers.

The term “pharmaceutically acceptable prodrugs” as used hereinrepresents those prodrugs of the compounds of the present invention thatare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use, as well as thezwitterionic forms, where possible, of the compounds of the invention. Adiscussion is provided in Higuchi et al., “Pro-drugs as Novel DeliverySystems,” ACS Symposium Series, Vol. 14, and in Roche, E. B., ed.Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “pharmaceutically acceptable salt(s)” refers to salts of acidicor basic groups that may be present in compounds used in the presentcompositions. Compounds included in the present compositions that arebasic in nature are capable of forming a wide variety of salts withvarious inorganic and organic acids. The acids that may be used toprepare pharmaceutically acceptable acid addition salts of such basiccompounds are those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfate, citrate, matate, acetate, oxalate, chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate,tannate, pantothenate, bitartrate, ascorbate, succinate, maleate,gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,benzoate, glutamate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds includedin the present compositions that include an amino moiety may formpharmaceutically acceptable salts with various amino acids, in additionto the acids mentioned above. Compounds included in the presentcompositions, that are acidic in nature are capable of forming basesalts with various pharmacologically acceptable cations. Examples ofsuch salts include alkali metal or alkaline earth metal salts and,particularly, calcium, magnesium, sodium, lithium, zinc, potassium, andiron salts.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers by wellknown methods, such as chiral-phase gas chromatography, chiral-phasehigh performance liquid chromatography, crystallizing the compound as achiral salt complex, or crystallizing the compound in a chiral solvent.Stereoisomers can also be obtained from stereomerically-pureintermediates, reagents, and catalysts by well known asymmetricsynthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The present invention encompasses the various geometricisomers and mixtures thereof resulting from the arrangement ofsubstituents around a carbon-carbon double bond or arrangement ofsubstituents around a carbocyclic ring. Substituents around acarbon-carbon double bond are designated as being in the “Z” or “E”configuration wherein the terms “Z” and “E” are used in accordance withIUPAC standards. Unless otherwise specified, structures depicting doublebonds encompass both the E and Z isomers. For example, the structurebelow represents a genus of alkenes in which the double bond is eitheran “E-double bond” or a “Z-double bond.”

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

EMBODIMENTS OF THE INVENTION

Disclosed herein are methods for increasing expression of ApoA-I in amammal comprising administering a therapeutically effective amount of acompound of Formula I:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂,wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ areeach independently selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or 6-membered ringto form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then pis 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond;

wherein if Y is O, then X is not CO;

wherein if X is O, the Z₁ is a single bond;

wherein if X is O and Z₂ is a single bond, then R₁₀ is not hydroxyl orester;

and pharmaceutically acceptable salts and hydrates thereof.

An alternative embodiment provides flavanoid compounds of Formula 1:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, and R17 areindependently selected from the group consisting of (C₁-C₂₂)alkyl,(C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl, heteroaryl, alkoxy, aryloxy,benzyl, phenyl, carbonyl, thioketone, hydrogen, hydroxyl [OH], acetyl,hydroxyalkyl, aminoalkyl, amides, carbamates, halogen, bromide [Br],iodide [I], fluoride [F], chloride [Cl], CF₃, CCl₃, sulfonic acid[—SO₃H], phosphate, O-sulfate [the sulfate conjugate], O-glucoronidate[the glucoronic (AKA glucuronic) acid conjugates], monoesters,dicarboxylic acid, #STR55#, #STR66#, #STR77#, #STR88#, #STR99#,#STR100#,

wherein W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 1:

wherein the same applies to any W;

or

wherein the same applies to any W:

wherein

X can be CH, CH₂, CR11, CR13, CHR11, CHR13, CR11R13, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Y can be CH, CH₂, CR12, CR14, CHR12, CHR14, CR11R14, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Z can be a single, double bond or triple bond, with the proviso that Xand Y do not exceed the number of valence electrons available as perdefinitions of X and Y above

Wherein

R15 and R16 are substituents independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen,hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates,halogen, bromide [Br], iodide [I], fluoride [F], chloride [Cl], CF₃,CCl₃, sulfonic acid [—SO₃H], phosphate, or a derivative thereof, whereinsaid derivative is optionally substituted and optionally branched, andmay have one or more of the C atoms replaced by S, N or O;

wherein Formula 1 compounds have at least one proviso selected from thefollowing

-   -   a. R7 is a hydroxyl;    -   b. at least one W is a N;    -   c. at least one of R1-R10 is #STR77#, #STR88# or #STR99#;    -   d. at least one of R1-R10 is #STR66#;    -   e. one of R1-R10 is a monoester;    -   f. one of R1-R10 is a dicarboxylic acid;    -   g. one of R1-R10 is succinic acid;    -   h. R7 is #STR55#;    -   i. R7 and R2 are #STR55#;    -   j. R7 and R2 are hydroxyls; and    -   k. R7 is #STR66#.

Non-limiting embodiments of Formula 1 include:

-   -   i. R7 is a hydroxyl and at least one W is a N;    -   ii. R7 is a hydroxyl and at least one of R1-R6 and R8-R10 is        #STR66#;    -   iii. R7 is a hydroxyl and at least one of R1-R6 and R8-R10 is        #STR77#, #STR88# or #STR99#; and    -   iv. R7 is #STR66# and at least one W is a N.

Other alternative embodiments of Formula 1 include

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, and R17 areindependently selected from the group consisting of (C₁-C₂₂)alkyl,(C₂-C₂₂)alkenyl, (C₁-C₂₂)alkynyl, aryl, heteroaryl, alkoxy, aryloxy,benzyl, phenyl, carbonyl, thioketone, hydrogen, hydroxyl [OH], acetyl,hydroxyalkyl, aminoalkyl, amides, carbamates, halogen, bromide [Br],iodide [I], fluoride [F], chloride [Cl], CF₃, CCl₃, sulfonic acid[—SO₃H], phosphate, O-sulfate [the sulfate conjugate], O-glucoronidate[the glucoronic (AKA glucuronic) acid conjugates], monoesters,dicarboxylic acid, #STR55#, #STR66#, #STR77#, #STR88#, #STR99#,#STR100#,

wherein W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 1:

wherein the same applies to any W;

or

wherein the same applies to any W:

wherein

X can be CH, CH₂, CR11, CR13, CHR11, CHR13, CR11R13, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Y can be CH, CH₂, CR12, CR14, CHR12, CHR14, CR11R14, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Z can be a single, double bond or triple bond, with the proviso that Xand Y do not exceed the number of valence electrons available as perdefinitions of X and Y above

wherein

R15 and R16 are substituents independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₁-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen,hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates,halogen, bromide [Br], iodide [I], fluoride [F], chloride [Cl], CF₃,CCl₃, sulfonic acid [—SO₃H], phosphate, or a derivative thereof, whereinsaid derivative is optionally substituted and optionally branched, andmay have one or more of the C atoms replaced by S, N or O;

wherein non limiting examples of Formula 1 have at least one provisoselected from the following:

R7 is a hydroxyl;

at least one W is a N;

at least one of R1-R10 is #STR77#, #STR88# or #STR99#;

at least one of R1-R10 is #STR66#;

one of R1-R10 is a monoester;

one of R1-R10 is a dicarboxylic acid;

one of R1-R10 is succinic acid;

R7 is #STR55#;

R7 and R2 are #STR55#;

R7 and R2 are hydroxyls; and

R7 is #STR66#.

Non-limiting examples include compounds of Formula 1 where

R7 is a hydroxyl and at least one W is a N;

R7 is a hydroxyl and at least one of R1-R6 and R8-R10 is #STR66#;

R7 is a hydroxyl and at least one of R1-R6 and R8-R10 is #STR77#,#STR88# or #STR99#; and

R7 is #STR66# and at least one W is a N.

Another embodiment provides flavanoid compounds of Formula 2:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 2:

wherein the same applies to any W;

or

or wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) R7 is a hydroxyl; or

b) R7 is a hydroxyl and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

e) at least one of R1-R10 is #STR66#.

Another embodiment provides compounds comprising the general flavonoidstructure of Formula 2:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 2:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) at least one W is a N and R7 is a hydroxyl; or

b) at least one W is a N and R7 is a hydroxyl, and optionally;

c) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

d) at least one of R1-R10 is #STR66#.

Another embodiment provides compounds comprising the general flavonoidstructure of Formula 2:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 2:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R7 is a hydroxyl; or

b) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R7 is a hydroxyl, and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-R10 is #STR66#.

Another embodiment provides compounds comprising the general flavonoidstructure of Formula 2:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 2:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁₁C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) R7 is a hydroxyl or #STR66# and if R7 is a hydroxyl (R1-R6 andR8-R10) at least one of R1-R10 is #STR66#; or

b) R7 is a hydroxyl or #STR66# and if R7 is a hydroxyl (R1-R6 andR8-R10) at least one of R1-R10 is #STR66# and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#.

Another embodiment provides compounds comprising the general flavonoidstructure of Formula 2:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 2:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) R7 is a hydroxyl or #STR66#, and

b) at least one W is a N, and

c) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and

d) at least one of R1-R10 is #STR66#.

Non-limiting examples of Formula 2 are provided below:

or pharmaceutically acceptable salts thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, R10, R14 and R15 are independentlyselected from the group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl,aryl, heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl,aminoalkyl, Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃],fluoride [F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [thesulfate conjugate], O-glucoronidate [the glucoronic (AKA glucuronic)acid conjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 2:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine;

R12 is (C₁₁C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

wherein Formula 2 compounds have at least one of the following groups ofprovisos:

1) with the proviso that;

a) R7 is a hydroxyl; or

b) R7 is a hydroxyl and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

e) at least one of R1-R10 is #STR66#.

2) with the proviso that;

a) at least one W is a N and R7 is a hydroxyl; or

b) at least one W is a N and R7 is a hydroxyl, and optionally;

c) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

d) at least one of R1-R10 is #STR66#.

3) with the proviso that;

a) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R7 is a hydroxyl; or

b) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R7 is a hydroxyl, and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-R10 is #STR66#.

4) with the proviso that;

a) R7 is a hydroxyl or #STR66# and if R7 is a hydroxyl at least one of(R1-R6 and R8-R10) is #STR66#; OR

b) R7 is a hydroxyl or #STR66# and if R7 is a hydroxyl at least one of(R1-R6 and R8-R10) is #STR66# and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#.

5) with the proviso that;

-   -   a) R7 is a hydroxyl or #STR66#, and    -   b) at least one W is a N, and    -   c) at least one of R-10 is #STR77#, or #STR88#, or #STR99#, and    -   d) at least one of R1-R10 is #STR66#.

Another alternative embodiment provides flavanoid compounds of Formula3:

and a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selectedfrom the group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates],

wherein

wherein

W can be C or N;

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein R13 is #STR100#, #STR77# or #STR99#

Wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine;

and R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or aderivative thereof, wherein said derivative is optionally substitutedand optionally branched, and may have one or more of the C atomsreplaced by S, N or O;

with the proviso that;

a) R7 is hydroxyl or #STR66# and at least one W is a N and optionally:

b) at least one of R1-R10 is #STR66#;

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 3:

and a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selectedfrom the group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates],

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein R13 is #STR100#, #STR77# or #STR99#

Wherein:

R11 is pyridine, pyridazine, pyrimidine, pyrazine;

and R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or aderivative thereof, wherein said derivative is optionally substitutedand optionally branched, and may have one or more of the C atomsreplaced by S, N or O;

with the proviso that

a) R7 is a hydroxyl and at least one of R1-10 is #STR66#; and/or

b) R7 is #STR66#.

Non-limiting examples of Formula 3 include

and a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selectedfrom the group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates],

wherein

wherein

W can be C or N;

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein R13 is #STR100#, #STR77# or #STR99#

Wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine;

and R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or aderivative thereof, wherein said derivative is optionally substitutedand optionally branched, and may have one or more of the C atomsreplaced by S, N or O;

with the proviso that;

a) R7 is hydroxyl or #STR66# and at least one W is a N and optionally:

b) at least one of R1-R10 is #STR66#;

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 3:

Non-limiting examples of Formula 3 include:

and a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, and R10 are independently selectedfrom the group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates],

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein R13 is #STR100#, #STR77# or #STR99#

Wherein:

R11 is pyridine, pyridazine, pyrimidine, pyrazine;

and R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or aderivative thereof, wherein said derivative is optionally substitutedand optionally branched, and may have one or more of the C atomsreplaced by S, N or O;

with the proviso that

a) R7 is a hydroxyl and at least one of R1-10 is #STR66#; and/or

b) R7 is #STR66#.

Disclosed herein are methods for increasing expression of ApoA-I in amammal comprising administering a therapeutically effective amount of acompound of Formula IV:

wherein:

X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and NR₁₁,wherein R₁₁ may be the same or different than R₁₃;

Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and NR₁₂,wherein R₁₂ may be the same or different than R₁₄;

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈are each independently selected from alkoxy, aryloxy, alkyl, alkenyl,alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide,sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone, or

two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₈ are connected in a 5 or 6-memberedring to form a bicyclic aryl or bicyclic heteroaryl;

each W is independently selected from C and N, wherein if W is N, then pis 0 and if W is C, then p is 1;

Z₁, Z₂ and Z₃ are each independently selected from a single bond and adouble bond;

wherein if Y is O, then X is not CO;

wherein if X is O, Y is CO and Z₂ is a double bond, then at least one ofR₅, R₆, R₈ and R₉ is not hydrogen;

and pharmaceutically acceptable salts and hydrates thereof.

An alternative embodiment provides isoflavanoid compounds of Formula 4:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R17 and R18are independently selected from the group consisting of (C₁-C₂₂)alkyl,(C₂-C₂₂)alkenyl, (C₁-C₂₂)alkynyl, aryl, heteroaryl, alkoxy, aryloxy,benzyl, phenyl, carbonyl, thioketone, hydrogen, hydroxyl [OH], acetyl,hydroxyalkyl, aminoalkyl, amides, carbamates, halogen, bromide [Br],iodide [I], fluoride [F], chloride [Cl], CF₃, CCl₃, sulfonic acid[—SO₃H], phosphate, O-sulfate [the sulfate conjugate], O-glucoronidate[the glucoronic (AKA glucuronic) acid conjugates], monoesters,dicarboxylic acid, #STR55#, #STR66#, #STR77#, #STR88#, #STR99#,#STR100#,

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 4:

wherein the same applies to any W;

or

wherein the same applies to any W:

wherein

X can be CH, CH₂, CR11, CR13, CHR11, CHR13, CR11R13, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Y can be CH, CH₂, CR12, CR14, CHR12, CHR14, CR11R14, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Z can be a single, double bond or triple bond, with the proviso that Xand Y do not exceed the number of valence electrons available as perdefinitions of X and Y above

wherein

R15 and R16 are substituents independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₁-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen,hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates,halogen, bromide [Br], iodide [I], fluoride [F], chloride [Cl], CF₃,CCl₃, sulfonic acid [—SO₃H], phosphate, or a derivative thereof, whereinsaid derivative is optionally substituted and optionally branched, andmay have one or more of the C atoms replaced by S, N or O;

wherein Formula 4 compounds have at least one proviso selected from thefollowing:

R8 is a hydroxyl;

at least one W is a N;

at least one of R1-R10 is #STR77#, #STR88# or #STR99#;

at least one of R1-R10 is #STR66#;

R8 is #STR66#;

one of R1-R10 is a monoester;

one of R1-R10 is a dicarboxylic acid;

R8 is #STR55#;

R8 and R3 are #STR55#;

R8 and R3 are hydroxyls; and

R8 is #STR66#.

Another embodiment provides for compounds of Formula 4 wherein:

R8 is a hydroxyl and at least one W is a N;

R8 is a hydroxyl and at least one of R1-R7 and R9-R-10 is #STR66#;

R8 is a hydroxyl and at least one of R1-R7 and R9-R10 is #STR77#,#STR88# or #STR99; and

R8 is #STR66# and at least one W is a N.

Non-limiting examples of compounds of Formula 4 include:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R17 and R18are independently selected from the group consisting of (C₁-C₂₂)alkyl,(C₂-C₂₂)alkenyl, (C₁-C₂₂)alkynyl, aryl, heteroaryl, alkoxy, aryloxy,benzyl, phenyl, carbonyl, thioketone, hydrogen, hydroxyl [OH], acetyl,hydroxyalkyl, aminoalkyl, amides, carbamates, halogen, bromide [Br],iodide [I], fluoride [F], chloride [Cl], CF₃, CCl₃, sulfonic acid[—SO₃H], phosphate, O-sulfate [the sulfate conjugate], O-glucoronidate[the glucoronic (AKA glucuronic) acid conjugates], monoesters,dicarboxylic acid, #STR55#, #STR66#, #STR77#, #STR88#, #STR99#,#STR100#,

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 4:

wherein the same applies to any W;

or

wherein the same applies to any W:

wherein

X can be CH, CH₂, CR11, CR13, CHR11, CHR13, CR11R13, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Y can be CH, CH₂, CR12, CR14, CHR12, CHR14, CR11R14, CO, CS, O, S, SO,SO₂, NH, NR11 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Z can be a single, double bond or triple bond, with the proviso that Xand Y do not exceed the number of valence electrons available as perdefinitions of X and Y above

wherein

R15 and R16 are substituents independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₁-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen,hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates,halogen, bromide [Br], iodide [I], fluoride [F], chloride [Cl], CF₃,CCl₃, sulfonic acid [—SO₃H], phosphate, or a derivative thereof, whereinsaid derivative is optionally substituted and optionally branched, andmay have one or more of the C atoms replaced by S, N or O;

wherein Formula 4 compounds have at least one proviso selected from thefollowing:

R8 is a hydroxyl;

at least one W is a N;

at least one of R1-R10 is #STR77#, #STR88# or #STR99#;

at least one of R1-R10 is #STR66#;

R8 is #STR66#;

one of R1-R10 is a monoester;

one of R1-R10 is a dicarboxylic acid;

R8 is #STR55#;

R8 and R3 are #STR55#;

R8 and R3 are hydroxyls; and

R8 is #STR66#.

Another embodiment provides for compounds of Formula 4 wherein:

R8 is a hydroxyl and at least one W is a N;

R8 is a hydroxyl and at least one of R1-R7 and R9-R-10 is #STR66#;

R8 is a hydroxyl and at least one of R1-R7 and R9-R10 is #STR77#,#STR88# or #STR99; and

R8 is #STR66# and at least one W is a N.

Another alternative embodiment provides isoflavanoid compounds ofFormula 5:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 5:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

Wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) R8 is a hydroxyl; or

b) R8 is a hydroxyl, and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

e) at least one of R1-R10 is #STR66#.

Another alternative embodiment provides compounds comprising theisoflavonoid structure of Formula 5:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 5

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R1 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁₁C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) at least one W is a N and R8 is a hydroxyl; OR

b) at least one W is a N and R8 is a hydroxyl, and optionally;

c) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

d) at least one of R1-R10 is #STR66#.

Another embodiment provides compounds comprising the isoflavonoidstructure of Formula 5:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 5

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R8 is a hydroxyl; or

b) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R8 is a hydroxyl, and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-R10 is #STR66#.

Another alternative embodiment provides compounds comprising the generalisoflavonoid structure of Formula 5:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 5.

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

Wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

a) R8 is a hydroxyl or #STR66# and if R8 is a hydroxyl at least one of(R1-R7 and R9-R10) is #STR66#; or

b) R8 is a hydroxyl or #STR66# and if R8 is a hydroxyl at least one of(R1-R7 and R9-R10) is #STR66# and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#.

Another alternative embodiment provides compounds comprising the generalisoflavonoid structure of Formula 5:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, and R10 are independently selected fromthe group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl,heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl,Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃], fluoride[F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [the sulfateconjugate], O-glucoronidate [the glucoronic (AKA glucuronic) acidconjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons. The structuresbelow demonstrate a nitrogen arrangement of one embodiment of thecompounds of Formula 5.

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

Wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

Wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

with the proviso that;

-   -   a) R8 is a hydroxyl or #STR66#, and    -   b) at least one W is a N, and    -   c) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and    -   d) at least one of R1-R10 is #STR66#.

Non-limiting examples of compounds of Formula 5 include:

or a pharmaceutically acceptable salts thereof,

wherein

R1, R2, R3, R4, R5, R6, R8, R9, R10, R14 and R15 are independentlyselected from the group consisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl,aryl, heteroaryl, hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl,aminoalkyl, Bromide [Br], Iodide [I], methoxy [OCH₃], ethoxy [OCH₂CH₃],fluoride [F], chloride [Cl], CF₃, CCl₃, phosphate, O-sulfate [thesulfate conjugate], O-glucoronidate [the glucoronic (AKA glucuronic)acid conjugates], #STR66#, #STR77#, #STR88#, #STR99#, #STR100#

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 5:

wherein the same applies to any W; or

wherein the same applies to any W:

wherein

wherein

X can be O, S, C, CR13, or NR13;

Y can be O, S, C, CR13, or NR13;

Z can be a single or a double bond

wherein

R13 is #STR77#, #STR88#, #STR99#, or #STR100#,

wherein

R11 is pyridine, pyridazine, pyrimidine, pyrazine; and

R12 is (C₁₁C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl or a derivativethereof, wherein said derivative is optionally substituted andoptionally branched, and may have one or more of the C atoms replaced byS, N or O;

wherein Formula 5 compounds have one at least one of the followinggroups of provisos:

1) with the proviso that;

a) R8 is a hydroxyl; or

b) R8 is a hydroxyl, and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

e) at least one of R1-R10 is #STR66#

2) with the proviso that;

a) at least one W is a N and R8 is a hydroxyl; or

b) at least one W is a N and R8 is a hydroxyl, and optionally;

c) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#, and/or;

d) at least one of R1-R10 is #STR66#

3) with the proviso that;

a) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R8 is a hydroxyl; or

b) at least one of R1-10 is selected from #STR77# or #STR88# or #STR99#,and R8 is a hydroxyl, and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-R10 is #STR66#.

4) with the proviso that;

a) R8 is a hydroxyl or #STR66# and if R8 is a hydroxyl at least one of(R1-R7 and R9-R10) is #STR66#; or

b) R8 is a hydroxyl or #STR66# and if R8 is a hydroxyl at least one of(R1-R7 and R9-R10) is #STR66# and optionally;

c) at least one W is a N, and/or;

d) at least one of R1-10 is #STR77#, or #STR88#, or #STR99#.

5) with the proviso that;

a) R8 is a hydroxyl or #STR66#, and

b) at least one W is a N, and

c) at least one of R-10 is #STR77#, or #STR88#, or #STR99#, and

d) at least one of R1-R10 is #STR66#.

Another alternative embodiment provides polyphenol compounds of Formula6:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16,R17, R18, R19 and R20 are independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, thioketone,hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides,carbamates, halogen, bromide [Br], iodide [I] fluoride [F], chloride[Cl], CF₃, CCl₃, sulfonic acid (—SO₃H), phosphate, O-sulfate [thesulfate conjugate], O-glucoronidate [the glucoronic (AKA glucuronic)acid conjugates], monoesters, dicarboxylic acid, #STR55#, #STR66#,#STR77#, #STR88#, #STR99#, #STR100#,

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 6:

wherein the same applies to any W;

or

wherein the same applies to any W:

wherein

X can be CH, CH₂, CR17, CR18, CHR17, CHR18, CR17R18, CO, CS, O, S, SO,SO₂, NH, NR17 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Y can be CH, CH₂, CR15CR16, CHR15, CHR16, CR15R16, CO, CS, O, S, SO,SO₂, NH, NR15 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Z can be a single or double bond with the proviso that X and Y do notexceed the number of valence electrons available as per definitions of Xand Y above

wherein

R21 and R12 are substituents independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen,hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates,halogen, bromide [Br], iodide [I], fluoride [F], chloride [Cl], CF₃,CCl₃, sulfonic acid (—SO₃H), phosphate, or a derivative thereof, whereinsaid derivative is optionally substituted and optionally branched, andmay have one or more of the C atoms replaced by S, N or O;

wherein Formula 6 compounds have at least one proviso selected from thefollowing:

R7 and R12 are a hydroxyl;

at least one W is a N;

at least one of R1-R14 is #STR77#, #STR88# or #STR99#;

at least one of R1-R14 is #STR66#;

R7 is #STR66#;

R12 is #STR66#;

one of R1-R14 is a monoester;

one of R1-R14 is a succinic acid;

one of R1-R14 is a dicarboxylic acid;

R7 is #STR55#;

R12 is #STR55#;

R7 and R12 are #STR55#; and

Another embodiment provides for compounds of Formula 6 wherein:

R7 is a hydroxyl and at least one W is a N;

R7 is a hydroxyl and at least one of R1-R6 and R8-R14 is #STR66#;

R7 is a hydroxyl and at least one of R1-R6 and R8-R14 is #STR77#,#STR88# and #STR99#;

R7 is #STR66# and at least one W is a N.

Non-limiting examples of compounds of Formula 6 include:

or a pharmaceutically acceptable salt thereof,

wherein

R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16,R17, R18, R19 and R20 are independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, thioketone,hydrogen, hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides,carbamates, halogen, bromide [Br], iodide [I], fluoride [F], chloride[Cl], CF₃, CCl₃, sulfonic acid (—SO₃H), phosphate, O-sulfate [thesulfate conjugate], O-glucoronidate [the glucoronic (AKA glucuronic)acid conjugates], monoesters, dicarboxylic acid, #STR55#, #STR66#,#STR77#, #STR88#, #STR99#, #STR100#,

wherein

W can be C or N;

wherein when W is an nitrogen atom, the nitrogen atom will only bind tothree covalent bonds due to available valence electrons.

The structures below demonstrate a nitrogen arrangement of oneembodiment of the compounds of Formula 6:

wherein the same applies to any W;

or

wherein the same applies to any W:

wherein

X can be CH, CH₂, CR17, CR18, CHR17, CHR18, CR17R18, CO, CS, O, S, SO,SO₂, NH, NR17 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Y can be CH, CH₂, CR15CR16, CHR15, CHR16, CR15R16, CO, CS, O, S, SO,SO₂, NH, NR15 with the proviso that X and Y do not exceed the number ofvalence electrons available as per definitions of X and Y above

Z can be a single or double bond with the proviso that X and Y do notexceed the number of valence electrons available as per definitions of Xand Y above

wherein

R21 and R12 are substituents independently selected from the groupconsisting of (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl,heteroaryl, alkoxy, aryloxy, benzyl, phenyl, carbonyl, hydrogen,hydroxyl [OH], acetyl, hydroxyalkyl, aminoalkyl, amides, carbamates,halogen, bromide [Br], iodide [I], fluoride [F], chloride [Cl], CF₃,CCl₃, sulfonic acid [—SO₃H], phosphate, or a derivative thereof, whereinsaid derivative is optionally substituted and optionally branched, andmay have one or more of the C atoms replaced by S, N or O;

wherein compounds have at least one proviso selected from the following:

R7 and R12 are a hydroxyl;

at least one W is a N;

at least one of R1-R14 is #STR77#, #STR88# or #STR99#;

at least one of R1-R14 is #STR66#;

R7 is #STR66#;

R12 is #STR66#

one of R1-R14 is a monoester;

one of R1-R14 is a succinic acid;

one of R1-R14 is a dicarboxylic acid;

R7 is #STR55#;

R12 is #STR55#

R7 and R12 are #STR55#; and

Another embodiment provides for compounds of Formula 6 wherein:

R7 is a hydroxyl and at least one W is a N;

R7 is a hydroxyl and at least one of R1-R6 and R8-R14 is #STR66#;

R7 is a hydroxyl and at least one of R1-R6 and R8-R14 is #STR77#,#STR88# and #STR99#;

R7 is #STR66# and at least one W is a N.

The following is a list of specific exemplary embodiments areencompassed by the invention:

1. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula I:

wherein:

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and        NR₁₁, wherein R₁₁ may be the same or different than R₁₃;    -   Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and        NR₁₂, wherein R₁₂ may be the same or different than R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and        R₁₇ are each independently selected from alkoxy, aryloxy, alkyl,        alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,        carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone,        nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,        sulfonamide and thioketone, or    -   two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆,        R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or        6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;    -   each W is independently selected from C and N, wherein if W is        N, then p is 0 and if W is C, then p is 1;    -   Z₁, Z₂ and Z₃ are each independently selected from a single bond        and a double bond;    -   wherein if Y is O, then X is not CO;    -   wherein if X is O, the Z₁ is a single bond;    -   wherein if X is O and Z₂ is a single bond, then R₁₀ is not        hydroxyl or ester;    -   and pharmaceutically acceptable salts and hydrates thereof.

2. The method of embodiment 1, wherein X is O and Y is CO.

3. The method of embodiment 1, wherein at least one W is N.

4. The method of embodiment 3, wherein X is O and Y is CO.

5. The method of embodiment 1, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromO-sulfate and O-glucoronidate.

6. The method of embodiment 1, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromsuccinate, D-argininate, L-argininate, L-lysinate and D-lysinate.

7. The method of embodiment 1, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromamide, amino, carbamate, carboxy, ester, ether, formyl, and ketone.

8. The method of embodiment 7, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is a nicotinateester.

9. The method of embodiment 1, wherein at least one W in the A ring ofFormula I is N.

10. The method of embodiment 1, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

11. The method of embodiment 10, wherein X is O and Y is CO.

12. The method of embodiment 10, wherein at least one W is N.

13. The method of embodiment 12, wherein X is O and Y is CO.

14. The method of embodiment 1, wherein Z₁ and Z₃ are single bonds, andZ₂ is a double bond.

15. The method of embodiment 14, wherein X is O and Y is CO.

16. The method of embodiment 14, wherein at least one W is N.

17. The method of embodiment 16, wherein X is O and Y is CO.

18. The method of embodiment 14, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

19. The method of embodiment 18, wherein X is O and Y is CO.

20. The method of embodiment 18, wherein at least one W is N.

21. The method of embodiment 20, wherein X is O and Y is CO.

22. The method of embodiment 1, wherein

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, and O; and    -   Y is selected from CR₁₂, CR₁₂R₁₄, S, SO, SO₂, and NR₁₂.

23. The method of embodiment 22, wherein at least one W is N.

24. The method of embodiment 22, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

25. The method of embodiment 24, wherein at least one W is N.

26. The method of embodiment 22, wherein Z₁ and Z₃ are single bonds, andZ₂ is a double bond.

27. The method of embodiment 26, wherein at least one W is N.

28. The method of embodiment 26, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

29. The method of embodiment 28, wherein at least one W is N.

30. The method of embodiment 1, wherein Formula I has the structure:

31. The method of embodiment 30, wherein X is O and Y is CO.

32. The method of embodiment 30, wherein at least one W is N.

33. The method of embodiment 32, wherein X is O and Y is CO.

34. The method of embodiment 30, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromO-sulfate and O-glucoronidate.

35. The method of embodiment 30, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromsuccinate, D-argininate, L-argininate, L-lysinate and D-lysinate.

36. The method of embodiment 30, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromamide, amino, carbamate, carboxy, ester, ether, formyl, and ketone.

37. The method of embodiment 36, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is a nicotinateester.

38. The method of embodiment 30, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

39. The method of embodiment 38, wherein X is O and Y is CO.

40. The method of embodiment 38, wherein at least one W is N.

41. The method of embodiment 40, wherein X is O and Y is CO.

42. The method of embodiment 30, wherein Z₁ and Z₃ are single bonds, andZ₂ is a double bond.

43. The method of embodiment 42, wherein X is O and Y is CO.

44. The method of embodiment 42, wherein at least one W is N.

45. The method of embodiment 44, wherein X is O and Y is CO.

46. The method of embodiment 42, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

47. The method of embodiment 46, wherein X is O and Y is CO.

48. The method of embodiment 46, wherein at least one W is N.

49. The method of embodiment 48, wherein X is O and Y is CO.

50. The method of embodiment 1, wherein Formula I has the structure:

51. The method of embodiment 50, wherein X is O and Y is CO.

52. The method of embodiment 50, wherein at least one W is N.

53. The method of embodiment 52, wherein X is O and Y is CO.

54. The method of embodiment 50, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromO-sulfate and O-glucoronidate.

55. The method of embodiment 50, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromsuccinate, D-argininate, L-argininate, L-lysinate and D-lysinate.

56. The method of embodiment 50, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromamide, amino, carbamate, carboxy, ester, ether, formyl, and ketone.

57. The method of embodiment 56, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is a nicotinateester.

58. The method of embodiment 50, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

59. The method of embodiment 58, wherein X is O and Y is CO.

60. The method of embodiment 58, wherein at least one W is N.

61. The method of embodiment 60, wherein X is O and Y is CO.

62. The method of embodiment 50, wherein Z₁ and Z₃ are single bonds, andZ₂ is a double bond.

63. The method of embodiment 62, wherein X is O and Y is CO.

64. The method of embodiment 62, wherein at least one W is N.

65. The method of embodiment 64, wherein X is O and Y is CO.

66. The method of embodiment 62, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

67. The method of embodiment 66, wherein X is O and Y is CO.

68. The method of embodiment 66, wherein at least one W is N.

69. The method of embodiment 68, wherein X is O and Y is CO.

70. The method of embodiment 1, wherein Formula I has the structure:

71. The method of embodiment 70, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

72. The method of embodiment 70, wherein at least one W is N.

73. The method of embodiment 72, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

74. The method of embodiment 70, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromO-sulfate and O-glucoronidate.

75. The method of embodiment 70, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromsuccinate, D-argininate, L-argininate, L-lysinate and D-lysinate.

76. The method of embodiment 70, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is selected fromamide, amino, carbamate, carboxy, ester, ether, formyl, and ketone.

77. The method of embodiment 76, wherein at least one of R₁, R₂, R₃, R₄,R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₇ is a nicotinateester.

78. The method of embodiment 70, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

79. The method of embodiment 78, wherein X is CR₁₁, R₁ is hydrogen and Yis Co.

80. The method of embodiment 78, wherein at least one W is N.

81. The method of embodiment 80, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

82. The method of embodiment 70, wherein Z₁ and Z₃ are single bonds, andZ₂ is a double bond.

83. The method of embodiment 84, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

84. The method of embodiment 84, wherein at least one W is N.

85. The method of embodiment 86, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

86. The method of embodiment 82, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate, and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

87. The method of embodiment 86, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

88. The method of embodiment 86, wherein at least one W is N.

89. The method of embodiment 88, wherein X is CR₁₁, R₁₁ is hydrogen andY is Co.

90. The method of embodiment 70, wherein Formula I is selected fromFormulae IA-ID:

91. The method of embodiment 1, wherein the therapeutically effectiveamount of the compound of Formula I is administered with apharmaceutically acceptable carrier in a pharmaceutically acceptablecomposition.

92. The method of embodiment 1, wherein the therapeutically effectiveamount of the compound of Formula I is sufficient to establish aconcentration ranging from about 0.001 μM to about 100 μM in the mammal.

93. The method of embodiment 92, wherein the concentration ranges fromabout 1 μM to about 20 μM.

94. The method of embodiment 1, wherein the compound of Formula I is2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one.

95. The method of embodiment 1, wherein the compound is3-(4-hydroxyphenyl)-2H-isoquinolin-1-one.

96. The method of embodiment 1, wherein the compound is4-isoquinolin-3-yl-phenol.

97. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula II:

wherein:

-   -   X is selected from CH₂, CHR₁₁, CHR₁₃, CR₁₁R₁₃, CO, CS, O, S, SO,        SO₂, NH and NR₁₁, wherein R₁₁ may be the same or different than        R₁₃;    -   Y is selected from CH₂, CHR₁₂, CHR₁₄, CR₁₂R₁₄, CO, CS, O, S, SO,        SO₂, NH and NR₁₂, wherein R₁₂ may be the same or different than        R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and        R₁₇ are each independently selected from (C₁-C₂₂)alkyl,        (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl, heteroaryl, alkoxy,        aryloxy, benzyl, phenyl, carbonyl, thioketone, hydrogen,        hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, amide, carbamate,        halogen, CF₃, CCl₃, sulfonic acid, phosphate, O-sulfate,        O-glucoronidate, monoester, dicarboxylic acid, J, K, L, M, P and        Q;    -   each W is independently selected from C and N;    -   Z₂ is selected from a single bond and a double bond;

-   -   R₁₅ and R₁₆ are each independently selected from (C₁-C₂₂)alkyl,        (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl, heteroaryl, alkoxy,        aryloxy, benzyl, phenyl, carbonyl, hydrogen, hydroxyl, acetyl,        hydroxyalkyl, aminoalkyl, amide, carbamate, halogen, CF₃, CCl₃,        sulfonic acid and phosphate;    -   and pharmaceutically acceptable salts thereof;        subject to at least one proviso selected from:

1) R₇ is hydroxyl;

2) at least one W is N;

3) at least one of R₁-R₁₀ is selected from L, M and P;

4) at least one of R₁-R₁₀ is selected from K;

5) R₇ is K;

6) one of R₁-R₁₀ is a monoester;

7) one of R₁-R₁₀ is a dicarboxylic acid;

8) one of R₁-R₁₀ is succinic acid;

9) R₇ and R₂ are each hydroxyl;

10) R₇ is selected from J; and

11) R₇ and R₂ are each selected from J.

98. The method of embodiment 97, wherein if proviso 1 is selected, asecond proviso is selected from provisos 2-4 and 6-9.

99. The method of embodiment 97, wherein R₇ is hydroxyl and at least oneW is N.

100. The method of embodiment 97, wherein R₇ is hydroxyl and at leastone of R₁-R₆ and R₈-R₁₀ is K.

101. The method of embodiment 97, wherein R₇ is hydroxyl and at leastone of R₁-R₆ and R₈-R₁₀ is selected from L, M and P.

102. The method of embodiment 97, wherein R₇ is K and at least one W isN.

103. The method of embodiment 97, wherein Y is selected from CH₂, CHR₁₂,CHR₁₄, CR₁₂R₁₄, CO, CS, S, SO, SO₂, NH and NR₁₂, wherein R₁₂ may be thesame or different than R₁₄.

104. The method of embodiment 97, wherein the compound of Formula II is2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one.

105. The method of embodiment 97, wherein Formula II is selected fromFormulae IIA-IIS:

106. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound selectedfrom Formulae IIT to IIW:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₉, and R₁₀ are independently        selected from (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl,        hydrogen, hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, bromide,        iodide, methoxy, ethoxy, fluoride, chloride, CF₃, CCl₃,        phosphate, O-sulfate, O-glucoronidate, K, D, E, F, and G;    -   R₇ is selected from hydroxyl and K;    -   each W is independently selected from C and N;

and pharmaceutically acceptable salts thereof;subject to at least one proviso selected from

1) at least one W is N;

2) at least one of R₁₋₆ and R₈₋₁₀ is selected from D, E and F; and

3) at least one of R₁₋₆ and R₈₋₁₀ is selected from K.

107. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula III:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₉, and R₁₀ are each independently        selected from (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl,        hydrogen, hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, bromide,        iodide, methoxy, ethoxy, fluoride, chloride, CF₃, CCl₃,        phosphate, O-sulfate, O-glucoronidate, K, D, E, F and G;    -   R₇ is selected from hydroxyl and K;    -   each W is independently selected from C and N;    -   Z₂ is selected from a single bond and a double bond;    -   X is selected from O, S, C, CR₁₁ and NR₁₁;    -   Y is selected from O, S, C, CR₁₂ and NR₁₂;    -   R₁₁ and R₁₂ are each independently selected from D, E, F, and G;

-   -   R₁₅ is selected from pyridine, pyridazine, pyrimidine, and        pyrazine;    -   R₁₆ is selected from (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl and        heteroaryl;    -   and pharmaceutically acceptable salts thereof;        subject to at least one proviso selected from

1) at least one W is N;

2) at least one of R₁₋₆ and R₈₋₁₀ is selected from D, E and F; and

3) at least one of R₁₋₆ and R₈₋₁₀ is selected from K.

108. The method of embodiment 107, wherein R₇ is hydroxyl and at leastone of R₁₋₆ and R₈₋₁₀ is selected from K.

109. The method of embodiment 108, subject to at least one provisoselected from

-   -   1) at least one W is N; and    -   2) at least one of R₁₋₆ and R₈₋₁₀ is selected from D, E and F.

110. The method of embodiment 107, wherein at least one W is N, at leastone of R₁₋₆ and R₈₋₁₀ is selected from D, E and F, and at least one ofR₁₋₆ and R₈₋₁₀ is selected from K.

111. The method of embodiment 107, wherein X is O, Y is CR₁₂, and R₁₂ isG.

112. The method of embodiment 107, wherein the compound of Formula IIIis 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one.

113. The method of embodiment 107, wherein Formula III is selected fromFormulae IIIA-IIIH:

-   -   wherein R₁₃ and R₁₄ are each independently selected from        (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl, hydrogen,        hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, bromide, iodide,        methoxy, ethoxy, fluoride, chloride, CF₃, CCl₃, phosphate,        O-sulfate, O-glucoronidate, K, D, E, F and G.

114. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula III:

wherein

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₉ and R₁₀ are each independently        selected from (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl,        hydrogen, hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, bromide,        iodide, methoxy, ethoxy, fluoride, chloride, CF₃, CCl₃,        phosphate, O-sulfate, and O-glucoronidate;    -   R₇ is selected from hydroxyl and K;    -   each W is independently selected from C and N;    -   Z₂ is selected from a single bond and a double bond;    -   X is selected from O, S, C, CR₁₁ and NR₁₁;    -   Y is selected from O, S, C, CR₁₂ and NR₁₂;    -   R₁₁ and R₁₂ are each independently selected from D, F and G;

-   -   wherein if R₇ is hydroxyl, then at least one W is N and at least        one of R₁₆ and R₈₋₁₀ is selected from K, and    -   wherein if R₇ is K, then at least one W is N.

115. The method of embodiment 114, wherein X is O, Y is CR₁₂, and R₁₂ isG.

116. The method of embodiment 114, wherein Formula III has thestructure:

117. The method of embodiment 114, wherein Formula III is selected fromFormulae IIIJ to IIIP:

118. The method of embodiment 1, wherein the compound of Formula I isselected from

-   5,7-Difluoro-2-(4-methoxy-phenyl)-chromen-4-one,-   5,7-Difluoro-2-(4-hydroxy-phenyl)-chromen-4-one,-   2-(3,5-Difluoro-4-hydroxyphenyl)chromen-4-one,-   2-(4-Hydroxy-3,5-dimethylphenyl)chromen-4-one,-   2-(5-Methoxy-pyridin-2-yl)-chromen-4-one,-   2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one,-   2-(6-Hydroxy-pyridin-3-yl)-chromen-4-one,-   2-Pyridin-4-yl-chromen-4-one,-   2-(4-Methoxy-phenyl)-thiochromen-4-one,-   2-(4-Hydroxy-phenyl)-thiochromen-4-one,-   2-(4-Hydroxyphenyl)-3-methyl-4H-chromen-4-one,-   4-(6-Bromo-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate,-   1-(2-Nitro-4-methoxy-phenyl)-chromen-4-one,-   2-(4-Hydroxy-2-nitrophenyl)chromen-4-one,-   2-(2-Amino-4-methoxy-phenyl)-chromen-4-one,-   2-(2-Amino-4-hydroxy-phenyl)-chromen-4-one,-   N-[5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]acetamide,-   6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one,-   2-(2-Fluoro-4-hydroxyphenyl)chromen-4-one,-   2-(4-Hydroxyphenyl)-8-nitro-4H-chromen-4-one,-   2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one,-   2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one,-   2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-one,-   2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile,-   2-(4-Methoxy-phenyl)-chromen-4-one,-   2-(3-Fluoro-4-hydroxyphenyl)chromen-4-one,-   2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid,-   6-Hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one,-   6-((Dimethylamino)methyl)-2-(4-hydrophenyl)-4H-chromen-4-one,-   8-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,-   2-(4-Hydroxy-phenyl)-chromen-4-one,-   7-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,-   5-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,-   5,7-Dihydroxy-2-(4-hydroxy-phenyl)-chromen-4-one,-   5,7-Dihydroxy-2-phenyl-chromen-4-one,-   5-Hydroxy-2-phenyl-chromen-4-one,-   2-(4-Acetoxy-phenyl)-thiochromen-4-one,-   2-(4-Acetoxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one,-   2-(4-Hydroxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one,-   5,7-Dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one,-   5,7-Dihydroxy-2-(4-hydroxy-phenyl)-quinolin-4-one,-   2-(4-Hydroxy-phenyl)-1H-quinolin-4-one,-   2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one,-   2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,-   2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one,-   2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one,-   2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one,-   2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one,-   4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile,-   2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,-   2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one,-   2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one,-   2-(4-Hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one,-   2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-c]pyridine 7-oxide,-   2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-b]pyridine 8-oxide,-   2-(4-Hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one,-   2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[3,2-c]pyridine-6-oxide,-   3-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one,-   2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile,-   3-(Hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one,-   2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one,-   3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one,-   7-(3-Fluoro-4-hydroxyphenyl)-6-methyl-1,6-naphthyridin-5(6H)-one,-   3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1(2H)-one,-   2-Fluoro-4-(5-methoxy-1-(methylamino)isoquinolin-3-yl)phenol,-   4-Naphthalen-2-yl-phenol,-   6-Naphthalen-2-yl-pyridin-3-ol,-   3-(4-Hydroxyphenyl)naphthalene-1-ol,-   4-Isoquinolin-3-yl-phenol,-   4-(1,6-Naphthyridin-7-yl)phenol,-   2-(4-Hydroxy-phenyl)-[1,4]naphthoquinone,-   4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate,-   4-(Benzo[b][1,4]dioxin-2-yl)phenol,-   4-(4H-Chromen-2-yl)-phenol,-   2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one,-   6-Naphthalen-2-yl-pyridin-3-ol,-   2-(4-Ethoxycarbonyloxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester, nicotinic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester,-   Acetic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester,-   4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate,-   2-Amino-5-guanidino-pentanoic acid 4-(4-oxo-4H-chromen-2-yl)phenyl    ester,-   4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate,-   4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl    2-amino-5-guanidinopentanoate,-   2-(4-(Nicotinoyloxy)phenyl)-4-oxochroman-5,7-diyl dinicotinate, and-   2-(4-(Nicotinoyloxy)phenyl)-4-oxo-4H-chromene-5,7-diyl dinicotinate.

119. A method of treating or preventing cardiovascular, cholesterol orlipid related disorders comprising administering a therapeuticallyeffective amount of a compound of Formula I:

wherein:

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and        NR₁₁, wherein R₁₁ may be the same or different than R₁₃;    -   Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and        NR₁₂, wherein R₁₂ may be the same or different than R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and        R₁₇ are each independently selected from alkoxy, aryloxy, alkyl,        alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,        carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone,        nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,        sulfonamide and thioketone, or    -   two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆,        R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or        6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;    -   each W is independently selected from C and N, wherein if W is        N, then p is 0 and if W is C, then p is 1;    -   Z₁, Z₂ and Z₃ are each independently selected from a single bond        and a double bond;    -   wherein if Y is O, then X is not CO;    -   wherein if X is O, the Z₁ is a single bond;    -   wherein if X is O and Z₂ is a single bond, then R₁₀ is not        hydroxyl or ester;    -   and pharmaceutically acceptable salts and hydrates thereof.

120. The method of embodiment 119, wherein the cardiovascular,cholesterol or lipid related disorder is selected from

-   -   acute coronary syndrome, angina pectoris, arteriosclerosis,        atherosclerosis, carotid atherosclerosis, cerebrovascular        disease, cerebral infarction, congestive heart failure,        congenital heart disease, coronary heart disease, coronary        artery disease, coronary plaque stabilization, dyslipidemias,        dyslipoproteinemias, endothelium dysfunctions, familial        hypercholeasterolemia, familial combined hyperlipidemia,        hypertension, hyperlipidemia, intermittent claudication,        ischemia, ischemia reperfusion injury, ischemic heart diseases,        multi-infarct dementia, myocardial infarction, peripheral        vascular disease, restenosis, renal artery atherosclerosis,        rheumatic heart disease, stroke, thrombotic disorder, transitory        ischemic attacks, and lipoprotein abnormalities associated with        Alzheimer's disease, obesity, diabetes mellitus, syndrome X and        impotence.

121. The method of embodiment 118, wherein treating or preventing acholesterol disorder comprises decreasing blood cholesterol levels.

122. The method of embodiment 118, wherein treating or preventing acholesterol disorder comprises increasing blood ApoA-I levels.

123. The method of embodiment 118, wherein the therapeutically effectiveamount of the compound of Formula I is administered with apharmaceutically acceptable carrier in a pharmaceutically acceptablecomposition.

124. The method of embodiment 118, wherein the therapeutically effectiveamount of the compound of Formula I is sufficient to establish aconcentration ranging from about 0.001 μM to about 100 μM in the mammal.

125. The method of embodiment 124, wherein the concentration ranges fromabout 1 μM to about 20 μM.

126. The method of embodiment 118, wherein the compound of Formula I is2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one.

127. The method of embodiment 118, wherein the compound is3-(4-hydroxyphenyl)-2H-isoquinolin-1-one.

128. The method of embodiment 118, wherein the compound is4-isoquinolin-3-yl-phenol.

129. A compound of Formula I:

wherein

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, O, N and NR₁₁, wherein R₁₁        may be the same or different than R₁₃;    -   Y is selected from CR₁₂, CR₁₂R₁₄, CO, O, N and NR₁₂, wherein R₁₂        may be the same or different than R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄        are each independently selected from alkoxy, aryloxy, alkyl,        alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,        carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone,        nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,        sulfonamide and thioketone, or    -   two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆,        R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, and R₁₄ are connected in a 5 or        6-membered ring to form a bicyclic aryl or bicyclic heteroaryl;    -   each W is independently selected from C and N, wherein if W is        N, then p is 0 and if W is C, then p is 1;    -   at least one W is N;    -   Z₁, Z₂ and Z₃ are each independently selected from a single bond        and a double bond;    -   wherein if X is O and Z₂ is a single bond, then R₁₀ is not        hydroxyl or ester;    -   wherein if        -   a W in the C ring is selected from N and NR₁₀,        -   Z₁ is a double bond, and        -   R₅, R₆, R₈, and R₉ are each hydrogen,        -   then R₇ is not hydroxyl or alkoxy;    -   and pharmaceutically acceptable salts or hydrates thereof.

130. The compound of embodiment 129, wherein R₇ is hydroxyl.

131. The compound of embodiment 129, wherein at least one W in the Aring is N.

132. The compound of embodiment 131, wherein X is O, Y is CO and Z₂ is adouble bond.

133. The compound of embodiment 132, wherein R₅, R₆, R₈, R₉ and R₁₀ areeach hydrogen.

134. The compound of embodiment 129, wherein at least one W in the Bring is N.

135. The compound of embodiment 129, wherein the W in the C ring isselected from N and NR₁₀, where R₁₀ is selected from hydrogen andmethyl.

136. The compound of embodiment 135, wherein Z₁ is a double bond.

137. The compound of embodiment 136, wherein Z₃ is a double bond and theW in the A ring is N.

138. The compound of embodiment 135, wherein R₈ is halogen.

139. The compound of embodiment 129, wherein at least one of R₁, R₂, R₃and R₄ is alkoxy.

140. The compound of embodiment 129, wherein Y is CR₁₂ and R₁₂ is amino.

141. A pharmaceutical composition comprising a compound of embodiment129 and a pharmaceutically acceptable carrier.

142. A method of increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofembodiment 129.

143. A method of treating or preventing cardiovascular, cholesterol orlipid related disorders comprising administering a therapeuticallyeffective amount of a compound of embodiment 129.

144. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula IV:

wherein:

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and        NR₁₁, wherein R₁ may be the same or different than R₁₃;    -   Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and        NR₁₂, wherein R₁₂ may be the same or different than R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇        and R₁₈ are each independently selected from alkoxy, aryloxy,        alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,        carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,        halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,        hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,        sulfonic acid, sulfonamide and thioketone, or    -   two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆,        R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₈ are connected in a 5        or 6-membered ring to form a bicyclic aryl or bicyclic        heteroaryl;    -   each W is independently selected from C and N, wherein if W is        N, then p is 0 and if W is C, then p is 1;    -   Z₁, Z₂ and Z₃ are each independently selected from a single bond        and a double bond;    -   wherein if Y is O, then X is not CO;    -   wherein if X is O, Y is CO and Z₂ is a double bond, then at        least one of R₅, R₆, R₈ and R₉ is not hydrogen;    -   and pharmaceutically acceptable salts and hydrates thereof.

145. The method of embodiment 14, wherein X is O and Y is CO.

146. The method of embodiment 14, wherein at least one W is N.

147. The method of embodiment 146, wherein X is O and Y is CO.

148. The method of embodiment 146, wherein at least one W in the A ringof Formula IV is N.

149. The method of embodiment 14, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

150. The method of embodiment 149, wherein X is O and Y is CO.

151. The method of embodiment 149, wherein at least one W is N.

152. The method of embodiment 151, wherein X is O and Y is CO.

153. The method of embodiment 14, wherein Z₁ and Z₃ are single bonds,and Z₂ is a double bond.

154. The method of embodiment 153, wherein X is O and Y is CO.

155. The method of embodiment 153, wherein at least one W is N.

156. The method of embodiment 155, wherein X is O and Y is CO.

157. The method of embodiment 153, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

158. The method of embodiment 157, wherein X is O and Y is CO.

159. The method of embodiment 157, wherein at least one W is N.

160. The method of embodiment 159, wherein X is O and Y is CO.

161. The method of embodiment 14, wherein

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, and O; and    -   Y is selected from CR₁₂, CR₁₂R₁₄, S, SO, SO₂, and NR₁₂

162. The method of embodiment 161, wherein at least one W is N.

163. The method of embodiment 161, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

164. The method of embodiment 163, wherein at least one W is N.

165. The method of embodiment 161, wherein Z₁ and Z₃ are single bonds,and Z₂ is a double bond.

166. The method of embodiment 165, wherein at least one W is N.

167. The method of embodiment 165, wherein R₇ is hydroxyl, and R₆ and R₈are independently selected from

-   -   arylalkyl, carboxy, cyano, cycloalkyl, ester, formyl, halogen,        haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl,        hydroxyalkyl, hydroxyaryl, ketone, perfluoroalkyl,        perfluorocycloalkyl, perfluoroalkoxy, O-sulfate and        O-glucoronidate,    -   subject to the proviso that R₆ and R₈ are not both        simultaneously hydrogen.

168. The method of embodiment 167, wherein at least one W is N.

169. The method of embodiment 14, wherein at least one of R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈ is selectedfrom O-sulfate and O-glucoronidate.

170. The method of embodiment 14, wherein at least one of R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈ is selectedfrom succinate, D-argininate, L-argininate, L-lysinate and D-lysinate.

171. The method of embodiment 14, wherein at least one of R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈ is selectedfrom amide, amino, carbamate, carboxy, ester, ether, formyl, and ketone.

172. The method of embodiment 171, wherein at least one of R₁, R₂, R₃,R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇ and R₁₈ is anicotinate ester.

173. The method of embodiment 14, wherein the therapeutically effectiveamount of the compound of Formula I is administered with apharmaceutically acceptable carrier in a pharmaceutically acceptablecomposition.

174. The method of embodiment 14, wherein the therapeutically effectiveamount of the compound of Formula IV is sufficient to establish aconcentration ranging from about 0.001 μM to about 100 μM in the mammal.

175. The method of embodiment 16, wherein the concentration ranges fromabout 1 μM to about 20 μM.

176. The method of embodiment 14, wherein the compound of Formula IV is3-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one.

177. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula V:

wherein

-   -   X is selected from CH₂, CHR₁₁, CHR₁₃, CR₁₁R₁₃, CO, CS, O, S, SO,        SO₂, NH and NR₁₁, wherein R₁₁ may be the same or different than        R₁₃;    -   Y is selected from CH₂, CHR₁₂, CHR₁₄, CR₁₂R₁₄, CO, CS, O, S, SO,        SO₂, NH and NR₁₂, wherein R₁₂ may be the same or different than        R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇        and R₁₈ are each independently selected from (C₁-C₂₂)alkyl,        (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl, heteroaryl, alkoxy,        aryloxy, benzyl, phenyl, carbonyl, thioketone, hydrogen,        hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, amide, carbamate,        halogen, CF₃, CCl₃, sulfonic acid, phosphate, O-sulfate,        O-glucoronidate, monoester, dicarboxylic acid, J, K, L, M, P and        Q;    -   each W is independently selected from C and N;    -   Z₂ is selected from a single bond and a double bond;

-   -   R₁₅ and R₁₆ are each independently selected from (C₁-C₂₂)alkyl,        (C₂-C₂₂)alkenyl, (C₂-C₂₂)alkynyl, aryl, heteroaryl, alkoxy,        aryloxy, benzyl, phenyl, carbonyl, hydrogen, hydroxyl, acetyl,        hydroxyalkyl, aminoalkyl, amide, carbamate, halogen, CF₃, CCl₃,        sulfonic acid and phosphate;    -   and pharmaceutically acceptable salts thereof;        subject to at least one proviso selected from:    -   1) R₇ is hydroxyl;    -   2) at least one W is N;    -   3) at least one of R₁-R₁₀ is selected from L, M and P;    -   4) at least one of R₁-R₁₀ is selected from K;    -   5) R₇ is K;    -   6) one of R₁-R₁₀ is a monoester;    -   7) one of R₁-R₁₀ is a dicarboxylic acid;    -   8) one of R₁-R₁₀ is succinic acid;    -   9) R₇ and R₂ are each hydroxyl; and    -   10) R₇ is selected from J.

178. The method of embodiment 177, wherein if proviso 1 is selected, asecond proviso is selected from provisos 2-4 and 6-9.

179. The method of embodiment 177, wherein R₇ is hydroxyl and at leastone W is N.

180. The method of embodiment 177, wherein R₇ is hydroxyl and at leastone of R₁-R₆ and R₈-R₁₀ is K.

181. The method of embodiment 177, wherein R₇ is hydroxyl and at leastone of R₁-R₆ and R₈-R₁₀ is selected from L, M and P.

182. The method of embodiment 177, wherein R₇ is K and at least one W isN.

183. The method of embodiment 177, wherein Y is selected from CH₂,CHR₁₂, CHR₁₄, CR₁₂R₁₄, CO, CS, S, SO, SO₂, NH and NR₁₂, wherein R₁₂ maybe the same or different than R₁₄.

184. The method of embodiment 177, wherein Formula V is selected fromFormulae VA to VK:

185. A method for increasing expression of ApoA-I in a mammal comprisingadministering a therapeutically effective amount of a compound ofFormula VI:

wherein:

-   -   R₁, R₂, R₃, R₄, R₅, R₆, R₈, R₉, and R₁₀ are independently        selected from (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl,        hydrogen, hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, bromide,        iodide, methoxy, ethoxy, fluoride, chloride, CF₃, CCl₃,        phosphate, O-sulfate, O-glucoronidate, K, D, E, F, and G;    -   R₇ is selected from hydroxyl and K;    -   each W is independently selected from C and N;    -   X is selected from O, S, C, CR₁₁ and NR₁₁;    -   Y is selected from O, S, C, CR₁₂ and NR₁₂;    -   R₁₁ and R₁₂ are each independently selected from D, E, F, and G;

-   -   R₁₅ is selected from pyridine, pyridazine, pyrimidine, and        pyrazine;    -   R₁₆ is selected from (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl and        heteroaryl;    -   and pharmaceutically acceptable salts thereof;        subject to at least one proviso selected from    -   1) at least one W is N;    -   2) at least one of R₁₋₆ and R₈₋₁₀ is selected from D, E and F;        and    -   3) at least one of R₁₋₆ and R₈₋₁₀ is selected from K.

186. The method of embodiment 185, wherein R₇ is hydroxyl and at leastone of R₁₋₆ and R₈₋₁₀ is selected from K.

187. The method of embodiment 186, subject to at least one provisoselected from

-   -   1) at least one W is N; and    -   2) at least one of R₁₋₆ and R₈₋₁₀ is selected from D, E and F.

188. The method of embodiment 185, wherein at least one W is N, at leastone of R₁₋₆ and R₈₋₁₀ is selected from D, E and F, and at least one ofR₁₋₆ and R₈₋₁₀ is selected from K.

189. The method of embodiment 185, wherein X is O, Y is CR₁₂, and R₁₂ isG.

190. The method of embodiment 185, wherein Formula VI is selected fromFormulae VIA-VIH:

-   -   wherein R₁₃ and R₁₄ are each independently selected from        (C₁-C₂₂)alkyl, (C₂-C₂₂)alkenyl, aryl, heteroaryl, hydrogen,        hydroxyl, acetyl, hydroxyalkyl, aminoalkyl, bromide, iodide,        methoxy, ethoxy, fluoride, chloride, CF₃, CCl₃, phosphate,        O-sulfate, O-glucoronidate, K, D, E, F and G.

191. A method of treating or preventing cardiovascular, cholesterol orlipid related disorders comprising administering a therapeuticallyeffective amount of a compound of Formula IV:

wherein:

-   -   X is selected from CR₁₁, CR₁₁R₁₃, CO, CS, O, S, SO, SO₂, N and        NR₁₁, wherein R₁₁ may be the same or different than R₁₃;    -   Y is selected from CR₁₂, CR₁₂R₁₄, CO, CS, O, S, SO, SO₂, N and        NR₁₂, wherein R₁₂ may be the same or different than R₁₄;    -   R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₇        and R₁₈ are each independently selected from alkoxy, aryloxy,        alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,        carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,        halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,        hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,        sulfonic acid, sulfonamide and thioketone, or    -   two adjacent substituents selected from R₁, R₂, R₃, R₄, R₅, R₆,        R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄ and R₁₈ are connected in a 5        or 6-membered ring to form a bicyclic aryl or bicyclic        heteroaryl;    -   each W is independently selected from C and N, wherein if W is        N, then p is 0 and if W is C, then p is 1;    -   Z₁, Z₂ and Z₃ are each independently selected from a single bond        and a double bond;    -   wherein if Y is O, X is not CO;    -   wherein if X is O, Y is CO and Z₂ is a double bond, then at        least one of R₅, R₆, R₈ and R₉ is not hydrogen;    -   and pharmaceutically acceptable salts and hydrates thereof.

192. The method of embodiment 191, wherein the cardiovascular,cholesterol or lipid related disorder is selected from

-   -   acute coronary syndrome, angina pectoris, arteriosclerosis,        atherosclerosis, carotid atherosclerosis, cerebrovascular        disease, cerebral infarction, congestive heart failure,        congenital heart disease, coronary heart disease, coronary        artery disease, coronary plaque stabilization, dyslipidemias,        dyslipoproteinemias, endothelium dysfunctions, familial        hypercholeasterolemia, familial combined hyperlipidemia,        hypertension, hyperlipidemia, intermittent claudication,        ischemia, ischemia reperfusion injury, ischemic heart diseases,        multi-infarct dementia, myocardial infarction, peripheral        vascular disease, restenosis, renal artery atherosclerosis,        rheumatic heart disease, stroke, thrombotic disorder, transitory        ischemic attacks, and lipoprotein abnormalities associated with        Alzheimer's disease, obesity, diabetes mellitus, syndrome X and        impotence.

193. The method of embodiment 191, wherein treating or preventing acholesterol disorder comprises decreasing blood cholesterol levels.

194. The method of embodiment 191, wherein treating or preventing acholesterol disorder comprises increasing blood ApoA-I levels.

195. The method of embodiment 191, wherein the therapeutically effectiveamount of the compound of Formula IV is administered with apharmaceutically acceptable carrier in a pharmaceutically acceptablecomposition.

196. The method of embodiment 191, wherein the therapeutically effectiveamount of the compound of Formula IV is sufficient to establish aconcentration ranging from about 0.001 μM to about 100 μM in the mammal.

197. The method of embodiment 196, wherein the concentration ranges fromabout 1 μM to about 20 μM.

198. The method of embodiment 191, where in the therapeuticallyeffective amount of compound of Formula IV is sufficient to establish aconcentration range from about 1 mg/kg to 30 mg/kg in the mammal.

199. The method of embodiment 191, wherein the compound of Formula IV is3-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one.

Pharmaceutical Formulations and Methods of Treatment

The present disclosure also provides pharmaceutical compositionscomprising compounds as disclosed herein formulated together with one ormore pharmaceutically acceptable carriers. These formulations includethose suitable for oral, rectal, topical, buccal and parenteral (e.g.subcutaneous, intramuscular, intradermal, or intravenous)administration, although the most suitable form of administration in anygiven case will depend on the degree and severity of the condition beingtreated and on the nature of the particular compound being used.

Formulations suitable for oral administration may be presented indiscrete units, such as capsules, cachets, lozenges, or tablets, eachcontaining a predetermined amount of the compound as powder or granules;as a solution or a suspension in an aqueous or non-aqueous liquid; or asan oil-in-water or water-in-oil emulsion. As indicated, suchformulations may be prepared by any suitable method of pharmacy whichincludes the step of bringing into association the active compound andthe carrier or excipient (which may constitute one or more accessoryingredients). The carrier must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and must not bedeleterious to the recipient. The carrier may be a solid or a liquid, orboth, and may be formulated with the compound as a unit-doseformulation, for example, a tablet, which may contain from 0.05% to 95%by weight of the active compound. Other pharmacologically activesubstances may also be present including other compounds. Theformulations of the invention may be prepared by any of the well knowntechniques of pharmacy consisting essentially of admixing thecomponents.

For solid compositions, conventional nontoxic solid carriers include,for example, pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose,magnesium carbonate, and the like. Liquid pharmacologicallyadministrable compositions can, for example, be prepared by dissolving,dispersing, etc., an active compound as described herein and optionalpharmaceutical adjuvants in an excipient, such as, for example, water,saline, aqueous dextrose, glycerol, ethanol, and the like, to therebyform a solution or suspension. In general, suitable formulations may beprepared by uniformly and intimately admixing the active compound with aliquid or finely divided solid carrier, or both, and then, if necessary,shaping the product. For example, a tablet may be prepared bycompressing or molding a powder or granules of the compound, optionallywith one or more assessory ingredients. Compressed tablets may beprepared by compressing, in a suitable machine, the compound in afree-flowing form, such as a powder or granules optionally mixed with abinder, lubricant, inert diluent and/or surface active/dispersingagent(s). Molded tablets may be made by molding, in a suitable machine,the powdered compound moistened with an inert liquid diluent.

Formulations suitable for buccal (sub-lingual) administration includelozenges comprising a compound in a flavored base, usually sucrose andacacia or tragacanth, and pastilles comprising the compound in an inertbase such as gelatin and glycerin or sucrose and acacia.

Formulations of the present invention suitable for parenteraladministration comprise sterile aqueous preparations of the compounds,which are approximately isotonic with the blood of the intendedrecipient. These preparations are administered intravenously, althoughadministration may also be effected by means of subcutaneous,intramuscular, or intradermal injection. Such preparations mayconveniently be prepared by admixing the compound with water andrendering the resulting solution sterile and isotonic with the blood.Injectable compositions according to the invention may contain from 0.1to 5% w/w of the active compound.

Formulations suitable for rectal administration are presented asunit-dose suppositories. These may be prepared by admixing the compoundwith one or more conventional solid carriers, for example, cocoa butter,and then shaping the resulting mixture.

Formulations suitable for topical application to the skin may take theform of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.Carriers and excipients which may be used include Vaseline, lanoline,polyethylene glycols, alcohols, and combinations of two or more thereof.The active compound is generally present at a concentration of fromabout 0.1% to about 15% w/w of the composition, for example, from about0.5 to about 2%.

The amount of active compound administered may be dependent on thesubject being treated, the subject's weight, the manner ofadministration and the judgment of the prescribing physician. Forexample, a dosing schedule may involve the daily or semi-dailyadministration of the encapsulated compound at a perceived dosage ofabout 1 μg to about 1000 mg. In another embodiment, intermittentadministration, such as on a monthly or yearly basis, of a dose of theencapsulated compound may be employed. Encapsulation facilitates accessto the site of action and allows the administration of the activeingredients simultaneously, in theory producing a synergistic effect. Inaccordance with standard dosing regimens, physicians will readilydetermine optimum dosages and will be able to readily modifyadministration to achieve such dosages.

A therapeutically effective amount of a compound or compositiondisclosed herein can be measured by the therapeutic effectiveness of thecompound. Compounds of the invention may be administered in a dose ofabout 1 μg/kg to about 200 mg/kg daily; such as from about 1 μg/kg toabout 150 mg/kg, from about 1 mg/kg to about 200 mg/kg, from about 1μg/kg to about 100 mg/kg, from about 1 μg/kg to about 1 mg/kg, fromabout 50 μg/kg to about 200 mg/kg, from about 10 μg/kg to about 1 mg/kg,from about 10 μg/kg to about 100 μg/kg, from about 100 μg to about 10mg/kg, and from about 500 μg/kg to about 50 mg/kg. The dosages, however,may be varied depending upon the requirements of the patient, theseverity of the condition being treated, and the compound being used. Inone embodiment, the therapeutically effective amount of a disclosedcompound is sufficient to establish a maximal plasma concentrationranging from about 0.001 μM to about 100 μM, e.g., from about 1 μM toabout 20 μM. Preliminary doses as, for example, determined according toanimal tests, and the scaling of dosages for human administration isperformed according to art-accepted practices.

Toxicity and therapeutic efficacy can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio LD₅₀/ED₅₀.Compositions that exhibit large therapeutic indices are preferable.

The therapeutically effective dose can be estimated initially from cellculture assays. A dose may be formulated in animal models to achieve acirculating plasma concentration range that includes the IC₅₀ (i.e., theconcentration of the therapeutic which achieves a half-maximalinhibition of symptoms) as determined in cell culture assays or animalmodels. Levels in plasma may be measured, for example, by highperformance liquid chromatography. The effects of any particular dosagecan be monitored by a suitable bioassay. Examples of dosages are: about0.1×IC₅₀, about 0.5×IC₅₀, about 1×IC₅₀, about 5×IC₅₀, 10×IC₅₀, about50×IC₅₀, and about 100×IC₅₀.

Data obtained from the cell culture assays or animal studies can be usedin formulating a range of dosage for use in humans. Therapeuticallyeffective dosages achieved in one animal model may be converted for usein another animal, including humans, using conversion factors known inthe art (see, e.g., Freireich et al., Cancer Chemother. Reports50(4):219-244 (1966) and Table 1 for Equivalent Surface Area DosageFactors).

TABLE 1 To: Mouse Rat Monkey Dog Human From: (20 g) (150 g) (3.5 kg) (8kg) (60 kg) Mouse 1 ½ ¼ ⅙   1/12 Rat 2 1 ½ ¼ 1/7 Monkey 4 2 1 ⅗ ⅓ Dog 64 ⅗ 1 ½ Human 12 7 3 2 1

The dosage of such compounds lies preferably within a range ofcirculating concentrations that include the ED₅₀ with little or notoxicity. The dosage may vary within this range depending upon thedosage form employed and the route of administration utilized.Generally, a therapeutically effective amount may vary with thesubject's age, condition, and sex, as well as the severity of themedical condition in the subject. The dosage may be determined by aphysician and adjusted, as necessary, to suit observed effects of thetreatment.

In one embodiment, a compound as disclosed herein, or a pharmaceuticallyacceptable salt or hydrate thereof, is administered in combination withanother therapeutic agent. The other therapeutic agent can provideadditive or synergistic value relative to the administration of aflavanoid or isoflavanoid compound alone. The therapeutic agent can be,for example, a statin; a PPAR agonist, e.g., a thiazolidinedione orfibrate; a bile-acid-binding-resin; a niacin; a RXR agonist; ananti-obesity drug; a hormone; a tyrophostine; a sulfonylurea-based drug;a biguanide; an alpha-glucosidase inhibitor; apolipoprotein E; acardiovascular drug; an HDL-raising drug; an HDL enhancer; or aregulator of the apolipoprotein A-IV and/or apolipoprotein genes.

In one embodiment, a method of treating or preventing cardiovascular,cholesterol or lipid related disorders comprises administering atherapeutically effective amount of a disclosed compound. The disclosedcompound may be administered as a pharmaceutically acceptablecomposition, comprising a disclosed compound and a pharmaceuticallyacceptable carrier. Another embodiment provides methods for theprevention of a cardiovascular, cholesterol or lipid related disorder,comprising administering to a mammal a therapeutically effective amountof a presently disclosed compound or composition.

Exemplary cardiovascular, cholesterol or lipid related disordersinclude, but are not limited to acute coronary syndrome, anginapectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis,cerebrovascular disease, cerebral infarction, congestive heart failure,congenital heart disease, coronary heart disease, coronary arterydisease, coronary plaque stabilization, dyslipidemias,dyslipoproteinemias, endothelium dysfunctions, familialhypercholeasterolemia, familial combined hyperlipidemia, hypertension,hyperlipidemia, intermittent claudication, ischemia, ischemiareperfusion injury, ischemic heart diseases, multi-infarct dementia,myocardial infarction, peripheral vascular disease, restenosis, renalartery atherosclerosis, rheumatic heart disease, stroke, thromboticdisorder, transitory ischemic attacks, and lipoprotein abnormalitiesassociated with Alzheimer's disease, obesity, diabetes mellitus,syndrome X and impotence.

As used herein, the term “cardiovascular disease” refers to diseases anddisorders of the heart and circulatory system. These diseases are oftenassociated with dyslipoproteinemias and/or dyslipidemias. “Endotheliumdysfunction(s)” include, but are not limited to, dysfunctions affectingblood vessel elasticity; peripheral vascular disease; coronary heartdisease; myocardial infarcation; cerebral infarction and restenosis.“Syndrome X” or “Metabolic Syndrome(s)” include, but are not limited tohypertension and dyslipidemia/dyslipoproteinemia.

In one embodiment, “treatment” or “treating” refers to an ameliorationof a disease or disorder, or at least one discernible symptom thereof.In another embodiment, “treatment” or “treating” refers to anamelioration of at least one measurable physical parameter, notnecessarily discernible by the patient. In yet another embodiment,“treatment” or “treating” refers to inhibiting the progression of adisease or disorder, either physically, e.g., stabilization of adiscernible symptom, physiologically, e.g., stabilization of a physicalparameter, or both. In yet another embodiment, “treatment” or “treating”refers to delaying the onset of a disease or disorder. For example,treating a cholesterol disorder may comprise decreasing bloodcholesterol levels.

One embodiment provides a compound for administration to a patient, suchas a human, as a preventative measure against cardiovascular,cholesterol or lipid related disorder. As used herein, “prevention” or“preventing” refers to a reduction of the risk of acquiring a givendisease or disorder. In another embodiment, the present compositions areadministered as a preventative measure to a patient, such as a humanhaving a genetic predisposition to, for example, a cardiovasculardisease, a dyslipidemia, a dyslipoproteinemia, Alzheimer's Disease,hypertension, atherosclerosis, or inflammation.

In another embodiment, the compositions of the invention areadministered as a preventative measure to a patient having a non-geneticpredisposition to, for example, cardiovascular disease, a dyslipidemia,a dyslipoproteinemia, Alzheimer's Disease, hypertension,atherosclerosis, or inflammation. Examples of such non-geneticpredispositions include, but are not limited to, cardiac bypass surgeryand percutaneous transluminal coronary angioplasty, which often leads torestenosis, an accelerated form of atherosclerosis; diabetes in women,which often leads to polycystic ovarian disease; and cardiovasculardisease, which often leads to impotence. Accordingly, the presentcompositions may be used for the prevention of one disease or disorderand concurrently treating another (e.g., prevention of polycysticovarian disease while treating diabetes; prevention of impotence whiletreating a cardiovascular disease).

Angioplasty and open heart surgery, such as coronary bypass surgery, maybe required to treat cardiovascular diseases, such as atherosclerosis.These surgical procedures entail using invasive surgical devices and/orimplants, and are associated with a high risk of restenosis andthrombosis. Accordingly, the compounds of the invention may be used ascoatings on surgical devices (e.g., catheters) and implants (e.g.,stents) to reduce the risk of restenosis and thrombosis associated withinvasive procedures used in the treatment of cardiovascular diseases.

The present invention provides methods for the treatment or preventionof a dyslipidemia comprising administering to a patient atherapeutically effective amount of a presently disclosed compound. Inone embodiment, the compound is administered as a pharmaceuticallyacceptable composition. As used herein, the term “dyslipidemias” refersto disorders that lead to or are manifested by aberrant levels ofcirculating lipids. To the extent that levels of lipids in the blood aretoo high, the disclosed compounds or compositions may be administered toa patient to restore normal levels. Normal levels of lipids are reportedin medical treatises known to those of skill in the art.

Dyslipidemias which the disclosed compounds or compositions are usefulfor preventing or treating include but are not limited to hyperlipidemiaand low blood levels of high density lipoprotein (HDL) cholesterol.Hyperlipidemia includes, but is not limited to, familialhypercholesterolemia; familial combined hyperlipidemia; reduced ordeficient lipoprotein lipase levels or activity, including reductions ordeficiencies resulting from lipoprotein lipase mutations;hypertriglyceridemia; hypercholesterolemia; high blood levels of ketonebodies (e.g., beta-OH butyric acid); high blood levels of Lp(a)cholesterol; high blood levels of low density lipoprotein (LDL)cholesterol; high blood levels of very low density lipoprotein (VLDL)cholesterol and high blood levels of non-esterified fatty acids.

One embodiment provides methods for altering lipid metabolism in apatient, e.g., increasing the ratio of HDL to LDL in the blood of apatient, comprising administering to the patient a composition of theinvention in an amount effective alter lipid metabolism.

Another embodiment provides methods for the treatment or prevention of adyslipoproteinemia comprising administering to a patient atherapeutically effective amount of a disclosed compound or composition.As used herein, the term “dyslipoproteinemias” refers to disorders thatlead to or are manifested by aberrant levels of circulatinglipoproteins. To the extent that levels of lipoproteins in the blood aretoo high, the disclosed compounds or compositions are administered to apatient to restore normal levels. Conversely, to the extent that levelsof lipoproteins in the blood are too low, the disclosed compounds orcompositions are administered to a patient to restore normal levels.Normal levels of lipoproteins are reported in medical treatises known tothose of skill in the art.

Dyslipoproteinemias which the disclosed compounds or compositions areuseful for preventing or treating include, but are not limited to, highblood levels of LDL; high blood levels of apolipoprotein B (apo B); highblood levels of Lp(a); high blood levels of apo(a); high blood levels ofVLDL; low blood levels of HDL; reduced or deficient lipoprotein lipaselevels or activity, including reductions or deficiencies resulting fromlipoprotein lipase mutations; hypoalphalipoproteinemia; lipoproteinabnormalities associated with diabetes mellitus; lipoproteinabnormalities associated with obesity; lipoprotein abnormalitiesassociated with Alzheimer's Disease; and familial combinedhyperlipidemia.

One embodiment provides methods for elevating the levels of HDLassociated proteins, such as ApoA-I, in the blood of a mammal,comprising administering to the mammal a composition comprising adisclosed compound or composition in an amount effective to elevatelevels of HDL associated proteins in the mammal.

Another embodiment provides methods for the treatment or prevention ofAlzheimer's Disease, hypertension, and/or atherosclerosis, comprisingadministering to a mammal a therapeutically effective amount of adisclosed compound or composition. As used herein, “treatment orprevention of Alzheimer's Disease” encompasses treatment or preventionof lipoprotein abnormalities associated with Alzheimer's Disease.

“Diseases and conditions associated with diabetes mellitus” as definedherein comprise, but are not restricted to, hyperglycemia,hyperinsulinaemia, hyperlipidaemia, insulin resistance, impaired glucosemetabolism, obesity, diabetic retinopathy, macular degeneration,cataracts, diabetic nephropathy, glomerulosclerosis, diabeticneuropathy, erectile dysfunction, premenstrual syndrome, vascularrestenosis, ulcerative colitis, skin and connective tissue disorders,foot ulcerations, metabolic acidosis, arthritis, osteoporosis andimpaired glucose tolerance.

Preparation of Compounds

Flavanoid compounds may be represented by the general structure ofFormula A.

R_(a) may be selected from groups including, but not limited to, alkoxy,aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, nitro,phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide andthioketone. R_(b) may be selected from groups including, but not limitedto, alkyl, amino, cyano, halogen and hydrogen. R_(c) representssubstituents such as alkyl, alkoxy, halogen, hydroxyl and hydrogen. Itshould be appreciated that these designations are non-limiting examplesof the flavanoid compounds disclosed herein.

One of ordinary skill will appreciate that flavanoid compounds asdisclosed herein may be synthesized from readily available startingmaterials as outlined below.

Formula B represents a general formula for flavanoid compoundscomprising a phenyl-chromene:

Flavanoids of Formula B can be synthesized by the procedure of Scheme 1:

Acid chloride 2 (R_(d)=Cl) may be used directly in a reaction withacetophenone 1 to provide ester 3. The acid chloride may also begenerated in situ by exposing the carboxylic acid 2 (R_(d)═OH) to achlorinating agent such as POCl₃. Ester 3 can be converted into diketone4 via intramolecular rearrangement. Rearrangement may be achieved usinga catalytic amount of base, such as potassium t-butoxide, KOH, NaH andthe like. Cyclization of phenol 4 to flavanoid 5 can be achieved byheating phenol 4 in the presence of a strong protic (HCl, AcOH, Hi,ACOH, HBr, and mixtures thereof or Lewis (BBr₃) acid.

Flavanoid compounds can be synthesized following the procedure of Scheme2:

Diketone 10 may be prepared by first exposing methyl ketones 6 or 9 tobasic conditions, such as potassium t-butoxide, KOH, NaH and the like,to form the corresponding enolate. Then, reaction with acyl halide 8 or7 (X=Hal), respectively, affords diketone 10. Cyclization of diketone 10to flavanoid 5 may likewise be accomplished by a number of methods. WhenR_(e)═F, exposure of 10 to heat and a polar solvent results in ringclosure via nucleophilic aromatic substitution. Alternatively, strongprotic or Lewis acids may be used when R_(e)=alkoxy, SH, or NH₂.Exemplary acids include HCl, AcOH, HI, AcOH, HBr, BBr₃, and mixturesthereof.

Formula C represents flavanoid compounds comprising a naphthyl:

Flavanoids of Formula C can be prepared via the procedure of Scheme 3.

Arylation of naphthalene analog 11 with boronic acid (or boronic ester)12 occurs by a Pd-catalyzed Suzuki coupling. Suitable Pd catalystsinclude Pd(Ph₃)₄ along with non-phosphine Pd catalysts, such palladiumacetate. Other coupling procedures that may be used in the synthesis offlavanoid 13 include Stille coupling.

Formula D represents a general formula for isoflavanoid compounds:

Scheme 4 illustrates a general synthesis of compounds of Formula D.

Treatment of phenol 14 with boron trifluoride etherate and methanesulfonylchloride gives isoflavanoid 15. Variations of the Scheme 4procedure include the method described by Fokialakis et al., Chemistry &Biology 11: 397-406 (2004).

Prodrugs of flavanoid compounds can be prepared according to Scheme 5:

Prodrug esters 19 can be synthesized by treating phenol 16 with acidhalide 17. Suitable acid halides include acid chlorides and bromides.Alternatively, esterification of phenol 16 with acid 18 in the presenceof a carbodiimide, such as EDCl, affords ester 19.

EXAMPLES

Examples of flavanoid compounds of Formula I include, but are notlimited to, the following compounds:

a) 2-(4-Hydroxy-phenyl)-1H-quinolin-4-one

and its derivatives, including, but not limited to:

-   2-(2,4-Dihydroxy-phenyl)-1H-quinolin-4-one-   2-(3,4-Dihydroxy-phenyl)-1H-quinolin-4-one-   5-Hydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   6-Hydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   7-Hydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   8-Hydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   5,7-Dihydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   6,7-Dihydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   7,8-Dihydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   2-(2,4-Dihydroxy-phenyl)-7-hydroxy-1H-quinolin-4-one-   2-(3,4-Dihydroxy-phenyl)-7-hydroxy-1H-quinolin-4-one-   5,6-Dihydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   5,8-Dihydroxy-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   2-(2,4-Dihydroxy-phenyl)-5-hydroxy-1H-quinolin-4-one-   2-(3,4-Dihydroxy-phenyl)-5-hydroxy-1H-quinolin-4-one-   2-(2-Fluoro-4-hydroxy-phenyl)-1H-quinolin-4-one-   2-(3-Fluoro-4-hydroxy-phenyl)-1H-quinolin-4-one-   5-Fluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   6-Fluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   7-Fluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   8-Fluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   5,7-Difluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   6,7-Difluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   7,8-Difluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   7-Fluoro-2-(2-fluoro-4-hydroxy-phenyl)-1H-quinolin-one-   7-Fluoro-2-(3-fluoro-4-hydroxy-phenyl)-1H-quinolin-4-one-   5,6-Difluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   5,8-Difluoro-2-(4-hydroxy-phenyl)-1H-quinolin-4-one-   5-Fluoro-2-(2-fluoro-4-hydroxy-phenyl)-1H-quinolin-4-one-   5-Fluoro-2-(3-fluoro-4-hydroxy-phenyl)-1H-quinolin-4-one-   Nicotinic acid 5-hydroxy-2-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 2-hydroxy-5-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid 2-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-quinolin-5-yl    ester-   Nicotinic acid 2-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-quinolin-6-yl    ester-   Nicotinic acid 2-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-quinolin-7-yl    ester-   Nicotinic acid 2-(4-hydroxy-phenyl)-4-oxo-1,4-dihydro-quinolin-8-yl    ester

b) Nicotinic acid 4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester

and its derivatives, including, but not limited to:

-   Nicotinic acid 3-hydroxy-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 2-hydroxy-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(6-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(8-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-hydroxy-4-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,7-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(6,7-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(7,8-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,6-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,8-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid 3-fluoro-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 2-fluoro-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(8-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid 4-(8-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-fluoro-4-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    2-fluoro-4-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,7-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(6,7-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(7,8-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    3-fluoro-4-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    2-fluoro-4-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,6-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,7-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester-   Nicotinic acid    4-(5,8-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester

c) 2-(4-Hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid ethyl ester

and its derivatives, including, but not limited to:

-   2-(3,4-Dihydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid ethyl    ester-   5-Hydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   6-Hydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   7-Hydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   8-Hydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   5,7-Dihydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   6,7-Dihydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   7,8-Dihydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(3,4-Dihydroxy-phenyl)-7-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,6-Dihydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,8-Dihydroxy-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(3,4-Dihydroxy-phenyl)-5-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(3-Fluoro-4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   5-Fluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   6-Fluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   7-Fluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   8-Fluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acid    ethyl ester-   5,7-Difluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   6,7-Difluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   7,8-Difluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   7-Fluoro-2-(3-fluoro-4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,6-Difluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,8-Difluoro-2-(4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5-Fluoro-2-(3-fluoro-4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester

d) 4-Oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylicacid ethyl ester

and its derivatives, including but not limited to:

-   2-[3-Hydroxy-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5-Hydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   6-Hydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   7-Hydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   8-Hydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   7-Hydroxy-2-[3-hydroxy-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,7-Dihydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   6,7-Dihydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   7,8-Dihydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   5-Hydroxy-2-[3-hydroxy-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,6-Dihydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   5,8-Dihydroxy-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[3-Fluoro-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5-Fluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   6-Fluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   7-Fluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   8-Fluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   7-Fluoro-2-[3-fluoro-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,7-Difluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   6,7-Difluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   7,8-Difluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   5-Fluoro-2-[3-fluoro-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   5,6-Difluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester-   5,8-Difluoro-4-oxo-2-[4-(pyridine-3-carbonyloxy)-phenyl]-4H-quinoline-1-carboxylic    acid ethyl ester

e) [5-Hydroxy-2-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic acidethyl ester

and its derivatives, including but not limited to:

-   [3,5-Dihydroxy-2-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [2-(5,7-Dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(6,7-Dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(7,8-Dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [2-(5,6-Dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(5,8-Dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [3-Fluoro-5-hydroxy-2-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4-Fluoro-5-hydroxy-2-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [2-(5-Fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(6-Fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(7-Fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(8-Fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(5,7-Difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(6,7-Difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(7,8-Difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [3-Fluoro-2-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [4-Fluoro-2-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(5,6-Difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [2-(5,8-Difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [4-Fluoro-2-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester-   [4-Fluoro-2-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-5-hydroxy-phenyl]-carbamic    acid ethyl ester

f) Nicotinic acid3-ethoxycarbonylamino-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl ester

and its derivatives, including but not limited to:

-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(7-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    4-(5,7-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    4-(6,7-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    4-(7,8-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(5-hydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    4-(5,6-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    4-(5,8-dihydroxy-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-fluoro-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-fluoro-4-(4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-fluoro-4-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-fluoro-4-(7-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    4-(5,7-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    4-(6,7-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    4-(7,8-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-fluoro-4-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-fluoro-4-(5-fluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-phenyl    ester-   Nicotinic acid    4-(5,6-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester-   Nicotinic acid    4-(5,8-difluoro-4-oxo-1,4-dihydro-quinolin-2-yl)-3-ethoxycarbonylamino-phenyl    ester

g)2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylicacid ethyl ester

and its derivatives, including but not limited to:

-   2-(2-Ethoxycarbonylamino-4,5-dihydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-5-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-6-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-7-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-5-fluoro-4-hydroxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-5-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-6-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-7-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-(2-Ethoxycarbonylamino-4-hydroxy-phenyl)-7-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester

h)2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylicacid ethyl ester

and its derivatives:

-   2-[2-Ethoxycarbonylamino-5-hydroxy-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-6-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-7-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-8-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-5-hydroxy-4-(pyridine-3-carbonyloxy)-phenyl]-7-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5,7-dihydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-6,7-dihydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-7,8-dihydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-5-hydroxy-4-(pyridine-3-carbonyloxy)-phenyl]-5-hydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5,6-dihydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5,8-dihydroxy-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-5-fluoro-4-(pyridine-3-carbonyloxy)-phenyl]-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-6-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-7-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-8-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-5-fluoro-4-(pyridine-3-carbonyloxy)-phenyl]-7-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5,7-difluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-6,7-difluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-7,8-difluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-5-fluoro-4-(pyridine-3-carbonyloxy)-phenyl]-5-fluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5,6-difluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester-   2-[2-Ethoxycarbonylamino-4-(pyridine-3-carbonyloxy)-phenyl]-5,8-difluoro-4-oxo-4H-quinoline-1-carboxylic    acid ethyl ester

i) 2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one

and its derivatives, including but not limited to:

-   2-(2,4-Dihydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one-   2-(3,4-Dihydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one-   5-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one-   6-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one-   7-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one-   Nicotinic acid 4-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(5-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(6-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(7-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-hydroxy-4-oxo-4H-pyrano[2,3-b]pyridin-2-yl)-phenyl    ester

j) 2-(4-Hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one

and its derivatives, including but not limited to:

-   2-(2,4-Dihydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one-   2-(3,4-Dihydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one-   5-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one-   6-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one-   8-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one-   Nicotinic acid 4-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(5-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(6-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(8-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-hydroxy-4-oxo-4H-pyrano[2,3-c]pyridin-2-yl)-phenyl    ester

k) 2-(4-Hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one

and its derivatives, including but not limited to:

-   2-(2,4-Dihydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one-   2-(3,4-Dihydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one-   5-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one-   7-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one-   8-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one-   Nicotinic acid 4-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(5-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(7-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(8-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-pyrano-3,2-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-4H-pyrano3,2-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-hydroxy-4-oxo-4H-pyrano[3,2-c]pyridin-2-yl)-phenyl    ester

l) 2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one

and its derivatives, including but not limited to:

-   2-(2,4-Dihydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one-   2-(3,4-Dihydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one-   6-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one-   7-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one-   8-Hydroxy-2-(4-hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one-   Nicotinic acid 4-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(6-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(7-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl ester-   Nicotinic acid    4-(8-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-hydroxy-4-oxo-4H-pyrano[3,2-b]pyridin-2-yl)-phenyl    ester

m) 2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one

and its derivatives, including but not limited to:

-   2-(5,6-Dihydroxy-pyridin-2-yl)-chromen-4-one-   2-(3,5-Dihydroxy-pyridin-2-yl)-chromen-4-one-   2-(4,5-Dihydroxy-pyridin-2-yl)-5-hydroxy-chromen-4-one-   5-Hydroxy-2-(5-hydroxy-pyridin-2-yl)-chromen-4-one-   6-Hydroxy-2-(5-hydroxy-pyridin-2-yl)-chromen-4-one-   7-Hydroxy-2-(5-hydroxy-pyridin-2-yl)-chromen-4-one-   8-Hydroxy-2-(5-hydroxy-pyridin-2-yl)-chromen-4-one-   Nicotinic acid 6-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl ester-   Nicotinic acid 2-hydroxy-6-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid 5-hydroxy-6-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid 4-hydroxy-6-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid 6-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid 6-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid 6-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid 6-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   [5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl]-carbamic acid    ethyl ester-   [5,6-Dihydroxy-2-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl]-carbamic acid    ethyl ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl]-carbamic    acid ethyl ester-   Nicotinic acid    5-ethoxycarbonylamino-6-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-6-(4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid    5-ethoxycarbonylamino-6-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid    5-ethoxycarbonylamino-6-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid    5-ethoxycarbonylamino-6-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester-   Nicotinic acid    5-ethoxycarbonylamino-6-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-3-yl    ester

n) 2-(6-Hydroxy-pyridin-3-yl)-chromen-4-one

and its derivatives, including but not limited to:

-   2-(2,6-Dihydroxy-pyridin-3-yl)-chromen-4-one-   5-Hydroxy-2-(6-hydroxy-pyridin-3-yl)-chromen-4-one-   6-Hydroxy-2-(6-hydroxy-pyridin-3-yl)-chromen-4-one-   7-Hydroxy-2-(6-hydroxy-pyridin-3-yl)-chromen-4-one-   8-Hydroxy-2-(6-hydroxy-pyridin-3-yl)-chromen-4-one-   Nicotinic acid 5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl ester-   Nicotinic acid 4-hydroxy-5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid 6-hydroxy-5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid 5-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid 5-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid 5-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid 5-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   [6-Hydroxy-3-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl]-carbamic acid    ethyl ester-   [4,6-Dihydroxy-3-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl]-carbamic acid    ethyl ester-   [6-Hydroxy-3-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl]-carbamic    acid ethyl ester-   [6-Hydroxy-3-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl]-carbamic    acid ethyl ester-   [6-Hydroxy-3-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl]-carbamic    acid ethyl ester-   [6-Hydroxy-3-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl]-carbamic    acid ethyl ester-   [2-Hydroxy-5-(4-oxo-4H-chromen-2-yl)-pyridin-4-yl]-carbamic acid    ethyl ester-   [2,6-Dihydroxy-3-(4-oxo-4H-chromen-2-yl)-pyridin-4-yl]-carbamic acid    ethyl ester-   [2-Hydroxy-5-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-4-yl]-carbamic    acid ethyl ester-   [2-Hydroxy-5-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-4-yl]-carbamic    acid ethyl ester-   [2-Hydroxy-5-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-4-yl]-carbamic    acid ethyl ester-   [2-Hydroxy-5-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-4-yl]-carbamic    acid ethyl ester-   Nicotinic acid    4-ethoxycarbonylamino-5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl ester-   Nicotinic acid    4-ethoxycarbonylamino-6-hydroxy-5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    4-ethoxycarbonylamino-5-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    4-ethoxycarbonylamino-5-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    4-ethoxycarbonylamino-5-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    4-ethoxycarbonylamino-5-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    6-ethoxycarbonylamino-5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl ester-   Nicotinic acid    6-ethoxycarbonylamino-4-hydroxy-5-(4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    6-ethoxycarbonylamino-5-(5-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    6-ethoxycarbonylamino-5-(6-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    6-ethoxycarbonylamino-5-(7-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester-   Nicotinic acid    6-ethoxycarbonylamino-5-(8-hydroxy-4-oxo-4H-chromen-2-yl)-pyridin-2-yl    ester

o) 2-(4-Hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one

and its derivatives, including but limited to:

-   2-(2,4-Dihydroxy-phenyl)-benzo[e][1,3]oxazin-4-one-   2-(3,4-Dihydroxy-phenyl)-benzo[e][1,3]oxazin-4-one-   5-Hydroxy-2-(4-hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one-   6-Hydroxy-2-(4-hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one-   7-Hydroxy-2-(4-hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one-   8-Hydroxy-2-(4-hydroxy-phenyl)-benzo[e][1,3]oxazin-4-one-   Nicotinic acid 4-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   Nicotinic acid    4-(5-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   Nicotinic acid    4-(6-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   Nicotinic acid    4-(7-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   Nicotinic acid    4-(8-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl ester-   [5-Hydroxy-2-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-hydroxy-4-oxo-4H-benzo[e][1,3]oxazin-2-yl)-phenyl    ester

p) 7-(4-Hydroxy-phenyl)-pyrano[2,3-d]pyrimidin-5-one

and its derivatives, including but not limited to:

-   7-(2,4-Dihydroxy-phenyl)-pyrano[2,3-d]pyrimidin-5-one-   7-(3,4-Dihydroxy-phenyl)-pyrano[2,3-d]pyrimidin-5-one-   4-Hydroxy-7-(4-hydroxy-phenyl)-pyrano[2,3-d]pyrimidin-5-one-   2-Hydroxy-7-(4-hydroxy-phenyl)-pyrano[2,3-d]pyrimidin-5-one-   Nicotinic acid 4-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl ester-   Nicotinic acid    4-(4-hydroxy-5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl ester-   Nicotinic acid    4-(2-hydroxy-5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl ester-   [5-Hydroxy-2-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(4-hydroxy-5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(2-hydroxy-5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-hydroxy-5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(2-hydroxy-5-oxo-5H-pyrano[2,3-d]pyrimidin-7-yl)-phenyl    ester

q) 6-(4-Hydroxy-phenyl)-pyrano[3,2-d]pyrimidin-8-one

and its derivatives, including but not limited to:

-   6-(2,4-Dihydroxy-phenyl)-pyrano[3,2-d]pyrimidin-8-one-   6-(3,4-Dihydroxy-phenyl)-pyrano[3,2-d]pyrimidin-8-one-   2-Hydroxy-6-(4-hydroxy-phenyl)-pyrano[3,2-d]pyrimidin-8-one-   4-Hydroxy-6-(4-hydroxy-phenyl)-pyrano[3,2-d]pyrimidin-8-one-   Nicotinic acid 4-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl ester-   Nicotinic acid    4-(2-hydroxy-8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl ester-   Nicotinic acid    4-(2-hydroxy-8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl ester-   [5-Hydroxy-2-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(2-hydroxy-8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(4-hydroxy-8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(2-hydroxy-8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-hydroxy-8-oxo-8H-pyrano[3,2-d]pyrimidin-6-yl)-phenyl    ester

r) 6-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyrazin-8-one

and its derivatives, including, but not limited to:

-   6-(2,4-Dihydroxy-phenyl)-pyrano[2,3-b]pyrazin-8-one-   6-(3,4-Dihydroxy-phenyl)-pyrano[2,3-b]pyrazin-8-one-   2-Hydroxy-6-(4-hydroxy-phenyl)-pyrano[2,3-b]pyrazin-8-one-   3-Hydroxy-6-(4-hydroxy-phenyl)-pyrano[2,3-b]pyrazin-8-one-   Nicotinic acid 4-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl ester-   Nicotinic acid    3-hydroxy-4-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl ester-   Nicotinic acid    2-hydroxy-4-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl ester-   Nicotinic acid    4-(2-hydroxy-8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl ester-   Nicotinic acid    4-(3-hydroxy-8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl ester-   [5-Hydroxy-2-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [3,5-Dihydroxy-2-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [4,5-Dihydroxy-2-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(2-hydroxy-8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(3-hydroxy-8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl]-carbamic    acid ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(2-hydroxy-8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(3-hydroxy-8-oxo-8H-pyrano[2,3-b]pyrazin-6-yl)-phenyl    ester

s) [5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid ethylester

and its derivatives, including but not limited to:

-   [3,5-Dihydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid ethyl    ester-   [4,5-Dihydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid ethyl    ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid    ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid    ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid    ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic acid    ethyl ester-   [5-Hydroxy-2-(5,6-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(6,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(5,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-carbamic    acid ethyl ester

t) Carbonic acid ethyl ester 5-hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenylester

and its derivatives, including but not limited to:

-   Carbonic acid 3,5-dihydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl ester    ethyl ester-   Carbonic acid 4,5-dihydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl ester    ethyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(5-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(6-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(7-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(5,6-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(5,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(6,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(6,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Carbonic acid ethyl ester    5-hydroxy-2-(7,8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester

u) [5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid ethyl ester

and its derivatives, including but not limited to:

-   [3,5-Dihydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid ethyl    ester-   [4,5-Dihydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid ethyl    ester-   [5-Hydroxy-2-(5-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid    ethyl ester-   [5-Hydroxy-2-(6-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid    ethyl ester-   [5-Hydroxy-2-(7-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid    ethyl ester-   [5-Hydroxy-2-(8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic acid    ethyl ester-   [5-Hydroxy-2-(5,6-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic    acid ethyl ester-   [5-Hydroxy-2-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic    acid ethyl ester-   [5-Hydroxy-2-(5,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic    acid ethyl ester-   [5-Hydroxy-2-(6,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl]-acetic    acid ethyl ester

v) Nicotinic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester

and its derivatives, including but not limited to:

-   Nicotinic acid 3-hydroxy-4-(4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 2-hydroxy-4-(4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(6-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(7-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5,6-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(6,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(6,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(7,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 3-fluoro-4-(4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 2-fluoro-4-(4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5-fluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(6-fluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(7-fluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(8-fluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5,6-difluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5,7-difluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(5,8-difluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(6,7-difluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(6,8-difluoro-4-oxo-4H-chromen-2-yl)-phenyl ester-   Nicotinic acid 4-(7,8-difluoro-4-oxo-4H-chromen-2-yl)-phenyl ester

w) Nicotinic acid 3-ethoxycarbonylamino-4-(4-oxo-4H-chromen-2-yl)-phenylester

and its derivatives, including but not limited to:

-   Nicotinic acid    3-ethoxycarbonylamino-5-hydroxy-4-(4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-hydroxy-4-(4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5,6-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6,7-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6,8-dihydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7,8-hydroxy-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-5-fluoro-4-(4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    5-ethoxycarbonylamino-2-fluoro-4-(4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(5-fluoro-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(6-fluoro-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(7-fluoro-4-oxo-4H-chromen-2-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(8-fluoro-4-oxo-4H-chromen-2-yl)-phenyl    ester

Examples of isoflavanoid compounds of Formula 4 include, but are notlimited to, the following compounds.

a) 3-(4-Hydroxy-phenyl)-chromen-4-one

and its derivatives, including but not limited to:

-   3-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one-   3-(4-Hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one-   3-(4-Hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one-   3-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one-   3-(5-Hydroxy-pyridin-2-yl)-chromen-4-one-   3-(6-Hydroxy-pyridin-3-yl)-chromen-4-one-   3-(4-Hydroxy-phenyl)-benzo[e][1,2]oxazin-4-one-   Nicotinic acid 4-(4-oxo-4H-chromen-3-yl)-phenyl ester-   Nicotinic acid 4-(4-oxo-4H-pyrano[2,3-b]pyridin-3-yl)-phenyl ester-   Nicotinic acid 4-(4-oxo-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl ester-   Nicotinic acid 4-(4-oxo-4H-pyrano[3,2-c]pyridin-3-yl)-phenyl ester-   Nicotinic acid 4-(4-oxo-4H-pyrano[3,2-b]pyridin-3-yl)-phenyl ester-   Nicotinic acid 6-(4-oxo-4H-chromen-3-yl)-pyridin-3-yl ester-   Nicotinic acid 5-(4-oxo-4H-chromen-3-yl)-pyridin-2-yl ester

b) [5-Hydroxy-2-(4-oxo-4H-chromen-3-yl)-phenyl]-carbamic acid ethylester

and its derivatives:

-   [5-Hydroxy-2-(4-oxo-4H-pyrano[2,3-b]pyridin-3-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[3,2-c]pyridin-3-yl)-phenyl]-carbamic    acid ethyl ester-   [5-Hydroxy-2-(4-oxo-4H-pyrano[3,2-b]pyridin-3-yl)-phenyl]-carbamic    acid ethyl ester-   [6-Hydroxy-3-(4-oxo-4H-chromen-3-yl)-pyridin-2-yl]-carbamic acid    ethyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-chromen-3-yl)-phenyl ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[2,3-b]pyridin-3-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[2,3-c]pyridin-3-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[3,2-c]pyridin-3-yl)-phenyl    ester-   Nicotinic acid    3-ethoxycarbonylamino-4-(4-oxo-4H-pyrano[3,2-b]pyridin-3-yl)-phenyl    ester-   Nicotinic acid    6-ethoxycarbonylamino-5-(4-oxo-4H-chromen-3-yl)-pyridin-2-yl ester.

The following compounds were obtained from commercially availablesources (such as Indofine Chemical Company, Inc.):2-(4-hydroxyphenyl)-chromen-4-one;6-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one;5,7-dihydroxy-2-phenyl-4H-chromen-4-one;5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one;7-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one;7-hydroxy-2-phenyl-4H-chromen-4-one;5-hydroxy-2-phenyl-4H-chromen-4-one; 2-phenyl-4H-chromen-4-one;2-(3-hydroxyphenyl)-4H-chromen-4-one;7-methoxy-2-(4-hydroxyphenyl)-4H-chromen-4-one;2-(4-hydroxy-3-methoxyphenyl)-4H-chromen-4-one;5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chroman-4-one;5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one; and3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-4H-chromen-4-one.

Abbreviations used herein denote the following compounds, reagents andsubstituents: acetic acid (AcOH); 2,2′-azobisisobutyronitrile (AIBN);N-bromosuccinimide (NBS); N-tert-butoxycarbonyl (Boc);t-butyldimethylsilyl (TBDMS); m-chloroperoxybenzoic acid (mCPBA);dimethylaminopyridine (DMAP); dichloromethane (DCM); dimethylformamide(DMF); dimethylsulfoxide (DMSO); ethanol (EtOH); ethyl acetate (EtOAc);1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl);1-hydroxybenzotriazole (HOBt); iodomethane (MeI); lithiumhexamethyldisilazide (LHMDS); methanol (MeOH); methoxymethyl (MOM);tetrahydrofuran (THF).

Example 1

5,7-Difluoro-2-(4-methoxy-phenyl)-chromen-4-one

In a 100 mL 3-neck round-bottomed flask fitted with condenser andmagnetic stirrer were placed dry THF (20 mL) and p-methoxy acetophenone(0.386 g, 2.57 mmol) under nitrogen. To this solution, LHMDS (2.69 mL asa 1M solution in THF, 2.57 mmol) was added drop wise at 25° C. Aftercompletion of addition, the mixture was stirred for 30 min at rt, then2,4,6-trifluoro-benzoyl chloride (0.5 g, 2.57 mmol) in THF (5 mL) wasadded slowly at rt via syringe. The reaction mixture was stirredovernight at rt. The reaction was quenched with saturated NH₄Cl solution(10 mL). The organic layer was separated and aqueous layer was extractedwith EtOAc. The combined organic layer was dries over Na₂SO₄,concentrated to give crude product, which was purified by columnchromatography using 20% EtOAc in hexane, to give 215 mg of1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (27%).1-(2,4,6-trifluoro-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (100mg) in DMSO (2 mL) was heated at 100-110° C. for 1 h. Then the reactionmixture was cooled to rt and diluted with water. The product wasfiltered and dried to give 62 mg of5,7-difluoro-2-(4-methoxy-phenyl)-chromen-4-one (68%). MS (ES) m/z:289.07 (M+1); ¹⁹F-NMR (DMSO-d₆): δ −101.9, −109.2.

Example 2

5,7-Difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 5,7-Difluoro-2-(4-methoxyphenyl)-4H-chromen-4-one(0.425 g, 1.47 mmol), hydroiodic acid (10 mL) and acetic acid (5 mL).The reaction mixture was heated 110° C. for 4 h. The reaction mixturewas cooled to room temperature and diluted with water. The precipitatewas filtered off, washed with water and dried to give the title compound(220 mg, 54%). Selected data for the title compound: MS (ES) m/z: 275.10(M+1); ¹⁹F-NMR (DMSO-d₆): δ −106.2, −113.4.

Example 3

2-(2-Amino-4-hydroxy-phenyl)-4H-chromen-4-one

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxyacetophenone (2.76 g, 20.28 mmol),2-nitro-4-methoxybenzoic acid (4.0 g, 20.28 mmol) and pyridine (60 mL).POCl₃ (3.11 g, 20.28 mmol) was added slowly on cooling. The reactionmixture was stirred for 24 h at rt under nitrogen. The reaction mixturewas poured into ice-water and extracted with ethyl acetate. The organiclayer was washed with water, dried and concentrated to give2-acetylphenyl-4-methoxy-2-nitrobenzoate (6.24 g, 97%).

To a solution of 2-acetylphenyl-4-methoxy-2-nitrobenzoate (6.22 g, 19.71mmol) in THF (100 mL), was added potassium t-butoxide (2.89 g, 23.65mmol) and the reaction mixture was stirred for 24 h at rt under N₂. Thereaction mixture was poured into a saturated aqueous solution of NH₄Cl.The organic layer was separated, washed with water, dried andconcentrated to give the crude compound, which was purified by columnchromatography using 50% ethyl acetate in hexane to give1-(2-hydroxyphenyl)-3-(4-methoxy-2-nitrophenyl)propane-1,3-dione (5.92g, 95%).

1-(2-Hydroxyphenyl)-3-(4-methoxy-2-nitrophenyl)propane-1,3-dione (5.92g, 18.77 mmol) was dissolved in a mixture of 48% HCl (2 mL) and aceticacid (35 mL) and heated at 100° C. for 1 h. The reaction mixture wascooled to rt, diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water, brine, dried and concentrated togive the crude compound, which was purified by column chromatographyusing 5% ethyl acetate in CH₂Cl₂ to give2-(4-methoxy-2-nitrophenyl)-4H-chromen-4-one (3.92 g, 70%).

2-(4-Methoxy-2-nitrophenyl)-4H-chromen-4-one (1.5 g, 5.04 mmol) wasdissolved in ethanol (30 mL) and heated at reflux. SnCl₂ (4.97 g 26.23mmol) was added. The mixture was heated under reflux for 20 min. Thereaction mixture was cooled to rt diluted with water, neutralized andextracted with ethyl acetate to give the crude compound. This waspurified by column chromatography using 3% MeOH in CH₂Cl₂ to give2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (790 mg, 58%).

To a 50 mL round-bottomed flask fitted with condenser and magneticstirrer was added 2-(2-amino-4-methoxyphenyl)-4H-chromen-4-one (770 mg,2.88 mmol), hydroiodic acid (10 mL) and acetic acid (4 mL). The reactionmixture was heated to 110° C. for 8 h. The reaction mixture was cooledto rt and diluted with water. The precipitate was filtered off, washedwith water and dried to give the crude compound, which was purified bycolumn chromatography using 2% MeOH in CH₂Cl₂, to give2-(2-amino-4-hydroxy-phenyl)-chromen-4-one (357 mg, 49%). MS (ES) m/z:254.05 (M+1), 149.00, 134.01, and 121.00.

Example 4

2-(4-Methoxy-phenyl)-4H-chromen-4-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxy acetophenone (1.0 g, 7.34 mmol) andpyridine (10 mL). To this mixture was added 4-methoxybenzoyl chloride(1.5 g, 8.81 mmol) and DMAP as a catalyst. The reaction was stirred forovernight at rt. The reaction mixture was poured into cold water andextracted with EtOAc. The combined organic layer was washed with water,brine, dried and solvent was removed afford 2-acetylphenyl4-methoxybenzoate (1.9 g, 95%).

To solution of 2-acetylphenyl 4-methoxybenzoate (1.907 g, 7.05 mmol) inpyridine (10 mL) was added powdered KOH (1.49 g, 21.16 mmol). Thereaction was stirred for 30 min at rt. The yellow viscous material wasdissolved in water, neutralized and extracted to give crude productwhich was purified by column chromatography using 30% EtOAc in hexane toafford 450 mg (23%) of1-(2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione.

To a solution of1-(2-hydroxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (200 mg,0.74 mmol) in dichloromethane (15 mL) was added BBr₃ (185 mg, 0.74 mmol,1M solution in dichloromethane) slowly at 0° C., and then stirred forovernight at rt. Then MeOH was added at 0° C. to quench the unreactedBBr₃. The organic layer was washed with water, dried and concentrated togive a crude product, which was purified by column chromatography using30% EtOAc in hexane to afford 50 mg (26%) of2-(4-methoxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 253.08 (M+1), and149.00.

Example 5

8-Hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one

To a solution of 4-methoxyacetophenone (2.0 g, 13.3 mmol) and methyl2,3-dimethoxybenzoate (3.135 g, 15.98 mmol) in DMF (100 mL), was added aNaH (1.065 g, 26.63 mmol) and the reaction mixture was stirred for 24 hat rt under N₂. The reaction mixture was poured into ice water andproducts were extracted with EtOAc. The organic layer was separated,washed with water, dried and concentrated to afford1-(2,3-dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g,74%).

1-(2,3-Dimethoxy-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (3.1 g,9.86 mmol) was dissolved in mixture of Hi (10 mL) and AcOH (10 mL) andheated at 110° C. for 4 days. The reaction mixture was cooled to rt,diluted with water and solids were filtered. The solid product waswashed with water, dried and purified by column chromatography, using30% EtOAc in dichloromethane to give 1.3 g (52%) of8-hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one. MS (ES) m/z: 255.08(M+1), and 154.15.

Example 6

2-(3,5-Difluoro-4-hydroxyphenyl)chromen-4-one

To a solution of 2′-hydroxyacetophenone (0.68 g, 5 mmol) in 10 mLanhydrous pyridine was added 3,5-difluoro-4-methoxybenzoyl chloride(1.03 g, 5 mmol) and the reaction mixture was stirred at rt for 15 hunder nitrogen atmosphere. The reaction mixture was poured into 100 mL2N HCl. The solid was filtered off, washed with water and dried undervacuum to give a white solid (1.44 g, 94%). The compound (1.42 g, 4.63mmol) was dissolved in 10 mL anhydrous pyridine. Powdered KOH (0.78 g,13.9 mmol) was added and the reaction mixture was stirred at rtovernight under nitrogen. Water (50 mL) was added and the solid wasisolated by filtration, and washed with water to give yellow solid (1.05g, 74%). To a suspension of the yellow solid (0.82 g, 2.67 mmol) in 6 mLglacial AcOH was added 3 drops of conc. HCl and the reaction mixture wasstirred at 110° C. for 2 h. The mixture was cooled to rt and 50 mL waterwas added. The solid was isolated by filtration, washed with water anddried under vacuum to give 2-(3,5-difluoro-4-methoxyphenyl)chromen-4-oneas a white solid (0.61 g, 79%).2-(3,5-Difluoro-4-methoxyphenyl)chromen-4-one was suspended in 15 mLhydroiodic acid. Glacial AcOH (6 mL) was added and the reaction mixturewas stirred at 110° C. for 4 h. The mixture was cooled to rt. Water (100mL) was added and the solid was isolated by filtration, washed withwater and dried under vacuum. The crude compound was washed with 1:1dichloromethane and MeOH (15 mL) to give2-(3,5-difluoro-4-hydroxyphenyl)-4H-chromen-4-one (0.416 g, 73%) as apale yellow solid. MS (ES) m/z: 275.04 (M+1); Mp. 275-276° C.

Example 7

2-(4-Hydroxy-3,5-dimethylphenyl)-4H-chromen-4-one

To a solution of 2-hydroxyacetophenone (1.361 g, 10 mmol) in 20 mLanhydrous pyridine was added 3,5-dimethyl-4-methoxybenzoic acid (2.162g, 12 mmol). The mixture was cooled to 0° C. and phosphorous oxychloride(1 mL) was added. A white precipitate was formed. The reaction mixturewas stirred at rt for 2 h under nitrogen atmosphere. Then the reactionmixture was poured into 100 mL cold 2N HCl and extracted with EtOAc(2×200 mL). The combined organic layers were washed with water and brineand dried over anhydrous Na₂SO₄. The solvent was removed under vacuum togive a colorless liquid (2.89 g, 97%), which was used in the next stepwithout further purification. The compound (2.88 g, 9.65 mmol) wasdissolved in 10 mL anhydrous pyridine. Powdered potassium hydroxide(1.62 g, 28.95 mmol) was added and the reaction mixture was stirred atrt overnight under nitrogen. Water (100 mL) was added and the mixturewas neutralized to pH 7 with conc. HCl. The yellow solid was filteredoff, washed with water and dried under vacuum. Yield: 1.16 g, 40%. To asuspension of the yellow solid (1.14 g, 3.83 mmol) in 8 mL glacial AcOHwas added 4 drops of conc. HCl and the reaction mixture was stirred at110° C. for 2 h. The mixture was cooled to rt and water (50 mL) wasadded. The solid was isolated by filtration and washed with water anddried under vacuum to give 2-(4-methoxy-3,5-dimethyl phenyl)chromen-4-one (1.05 g, 98%) as a pale green solid.2-(4-methoxy-3,5-dimethyl phenyl) chromen-4-one was suspended in 20 mLhydroiodic acid and 8 mL glacial AcOH was added. The reaction mixturewas stirred at 110° C. for 2 h. The mixture was cooled to rt. Water (100mL) was added and the solid was isolated by filtration, washed withwater and dried under vacuum. The crude compound was washed with 1:1dichloromethane and methanol (20 mL) to give 0.763 g of2-(4-hydroxy-3,5-dimethylphenyl)-4H-chromen-4-one (85%) as a pale yellowsolid. MS (ES) m/z: 267.06 (M+1); Mp. 255-256° C.

Example 8

N-[5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]acetamide

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(2-amino-4-hydroxy-phenyl)-chromen-4-one (150 mg,0.592 mmol), Ac₂O (181 mg, 1.776 mmol), and pyridine (5 mL) and then thereaction mixture was stirred for 24 h at rt. The reaction mixture waspoured into water and extracted with EtOAc. The organic layer washedwith water, dried and concentrated to give the intermediate (228 mg,99%). To a solution of the intermediate (228 mg, 0.676 mmol) in MeOH:THF(5 mL:5 mL), K₂CO₃ (112 mg, 0.811 mmol) was added and stirred for 2 h atrt. Then the reaction mixture was neutralized by dilute HCl andextracted by EtOAc, the combined organic layers were washed with water,brine, dried and concentrated to give a crude product, which waspurified by column chromatography using 2% MeOH in dichloromethane toafford N-[5-hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]acetamide (100 mg,50%). MS (ES) m/z: 296.15 (M+1); Mp. 253-255° C.

Example 9

1-[4-(6-Hydroxy-4-oxo-4H-chromen-2-yl)benzyl]pyridinium chloride

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxy-5′-methoxyacetophenone (2.0 g, 12.03mmol), 4-acetoxymethylbenzoic acid (2.4 g, 12.03 mmol) and pyridine (20mL). POCl₃ (1.8 g, 12.03 mmol) was added slowly on cooling. The reactionmixture was stirred for 24 h at rt under nitrogen. The reaction mixturewas poured into ice-water and extracted with EtOAc. The organic layerwas washed with water, dried and concentrated to give the product (3.08g, 72%). To a solution of this product (3.08 g, 8.99 mmol) in THF (50mL), was added potassium t-butoxide (1.32 g, 10.07 mmol) and thereaction mixture was stirred for 24 h at rt under N₂. The reactionmixture was poured into saturated aqueous NH₄Cl. The organic layer wasseparated, washed with water, dried and concentrated to give the crudediketone (3.07 g, 99%). The diketone compound (3.07 g, 8.96 mmol) wasdissolved in a mixture of 48% HCl (2 mL) and AcOH (20 mL) and heated at100° C. for 1 h. The reaction mixture was cooled to rt, diluted withwater and extracted with EtOAc. The organic layer was washed with water,brine, dried and concentrated to give cyclized product (1.38 g, 47%). Toa solution of the cyclized product (1.2 g, 3.69 mmol) in THF (30 mL),K₂CO₃ (613 mg, 4.44 mmol) was added and the mixture was stirredovernight at rt. Then the reaction mixture was neutralized by dilute HCland extracted by EtOAc, the combined organic layers were washed withwater, brine, dried and concentrated to give a crude product (548 mg,52%). A mixture of the 6-methoxyflavone analogue (400 mg, 1.41 mmol) andpyridinium hydrochloride (8 g) was heated at 190° C. for 4 h. Thereaction mixture was cooled to rt, diluted with water, neutralized withNaHCO₃ and filtered to give the crude product. This was purified bycrystallization using MeOH/dichloromethane/EtOAc to give 200 mg of1-[4-(6-hydroxy-4-oxo-4H-chromen-2-yl)benzyl]pyridinium chloride (51%).MS (ES) m/z: 330.89 (M), 329.86 (M−1); Mp. 243-247° C.

Example 10

2-(4-Hydroxy-2-nitrophenyl)chromen-4-one

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxyacetophenone (2.76 g, 20.28 mmol),2-nitro-4-methoxybenzoic acid (4.0 g, 20.28 mmol) and pyridine (60 mL).POCl₃ (3.11 g, 20.28 mmol) was added slowly on cooling. The reactionmixture was stirred for 24 h at rt under nitrogen. The reaction mixturewas poured into ice-water and extracted with ethyl acetate. The organiclayer was washed with water, dried and concentrated to give product(6.24 g, 97%). To a solution of the product (817 mg, 2.59 mmol) in THF(10 mL), was added potassium t-butoxide (380 mg, 3.11 mmol), and thereaction mixture was stirred for 24 h at rt under N₂. The reactionmixture was poured into a saturated aqueous solution of NH₄Cl. Theorganic layer was separated, washed with water, dried over Na₂SO₄ andconcentrated to give the diketone (800 mg, 97%).

The diketone compound (800 mg, 2.53 mmol) was dissolved in a mixture of48% HCl (1 mL) and acetic acid (7 mL) and heated at 100° C. for 1 h. Thereaction mixture was cooled to rt, diluted with water and extracted withethyl acetate. The organic layer was washed with water, brine, driedover Na₂SO₄ and concentrated to the crude product, which was purified bycrystallization to give (500 mg, 67%) of cyclized product. The product(500 mg, 1.68 mmol) and pyridinium hydrochloride (8 g) were mixed andheated at 190° C. for 4 h. The reaction mixture was cooled to rt,diluted with water, neutralized by NaHCO₃ and filtered to give2-(4-hydroxy-2-nitrophenyl)chromen-4-one (430 mg, 92%). MS (ES) m/z:284.88 (M+1), 283.86 (M); Mp. 277-279° C.

Example 11

6-Hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one

A suspension of 2′-hydroxyacetophenone (5 g) and paraformaldehyde (1.9g) in 20 mL of conc. HCl was stirred at 35° C. for 4 h, until theformation of a yellow precipitate.2′-Hydroxy-5′-chloromethylacetophenone was filtered off, air dried andused for the next step without further purification.2′-Hydroxy-5′-chloromethylacetophenone (6.8 g) was dissolved in 100 mLof dry MeOH and NaOMe (25 w % in MeOH, 15.9 g) was slowly added. Theresulting solution was stirred at rt overnight. After the reaction, 1MHCl was slowly added to neutralize the reaction mixture. The reactionmixture was dried by direct addition of anhydrous MgSO₄ and concentratedby evaporation of the MeOH. The residue was loaded on a column with 20%EtOAc/Hexane as an eluent to isolate2′-hydroxy-5′-methoxymethylacetophenone (4.9 g, 74%).

A mixture of 2′-hydroxy-5′-methoxymethylacetophenone (1.2 g) and 20 mLof pyridine was stirred for 15 min, before the addition of4-methoxybenzoyl chloride (1.14 g). The formed solution was stirred atrt overnight. HCl (1M) was slowly added to neutralize the reactionsolution. Then 50 mL of water was added, and the resulting solution wasextracted by EtOAc (3×50 mL). The combined organic layers were driedover MgSO₄ and evaporated under vacuum. The residue was passed through asilica gel column quickly with 40% EtOAc/hexane as an eluent to affordbenzoate (1.46 g, 70%). To the solution of benzoate (2.3 g) in dry THF(30 mL) was slowly added NaH (0.92 g, 60% in mineral oil). The solutionwas heated to reflux overnight. The solution was cooled to rt andneutralized by adding 1M HCl. Water (50 mL) was added and the resultingsolution was extracted with EtOAc (3×50 mL). After drying the combinedorganic layers over MgSO₄ and evaporation of solvent, the product wasassayed by ¹H-NMR and the crude diketone was used directly in the nextstep reaction without further purification.

A mixture of the diketone (1.1 g), 30 mL of AcOH and 3 mL of conc. HClwas stirred at 105° C. for 15 min. Then water (30 mL) was added and theresulting solution was extracted by EtOAc (3×30 mL). The combinedorganic layers were dried over MgSO₄, evaporated under vacuum andpurified by column chromatography on silica gel (40% EtOAc/Hexane) toafford the cyclized compound (0.68 g, 66%). To the solution of thecyclized compound (0.6 g) in dichloromethane (20 mL), 10 mL of 1 M BBr₃were added slowly. The resulting black solution was stirred at rt for 24h. After the reaction, 50 mL of water was slowly added to the stirringsolution. Then 30 mL of EtOAc and Na₂CO₂ powder was added. After theneutralization, conc. HCl was used to acidify the solution to pH 2. Themixture was extracted with EtOAc (2×20 mL). The combined organic layerswere concentrated and purified by column chromatography on silica gel(5% MeOH/dichloromethane) to afford6-bromomethyl-2-(4-hydroxyphenyl)chromen-4-one (0.4 g, 60%).

To a solution of 6-bromomethyl-2-(4-hydroxyphenyl)chromen-4-one (250 mg,0.754 mmol) in dioxane:DMF (10:2, 12 mL), was added potassium acetate(500 mg, 3.77 mmol). The mixture was heated at 100° C. for 3 h. Thereaction mixture was diluted with water and extracted with EtOAc. Thecombined organic layers were washed with water, brine, dried over Na₂SO₄and concentrated to give crude product (225 mg, 96%). To a solution ofthe crude product (220 mg, 0.711 mmol) in MeOH:THF (5 mL: 5 mL) wasadded K₂CO₃ (216 mg, 1.56 mmol) and the mixture was stirred for 24 h atrt. Then the reaction mixture was neutralized by dilute HCl andextracted by EtOAc, the combined organic layers were washed with water,brine, dried and concentrated to give a crude product, which waspurified by column chromatography using 5% MeOH in dichloromethane, toafford 6-hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one (80 mg, 42%). MS(ES) m/z: 269.88 (M+1), 268.85 (M); Mp. 246-247° C.

Example 12

2-(3-Fluoro-4-hydroxyphenyl)chromen-4-one

To a solution of 2′-hydroxyacetophenone (1.36 g, 10 mmol) in 20 mLanhydrous pyridine was added 3-fluoro-4-methoxybenzoyl chloride (1.89 g,10 mmol) and the reaction mixture was stirred at rt for 15 h under anitrogen atmosphere. The reaction mixture was poured into 200 mL of 2 NHCl. The formed solid was isolated by filtration, washed with water anddried under vacuum to give a white solid (2.76 g, 95.7%). The compound(2.68 g, 9.3 mmol) was dissolved in 10 mL anhydrous pyridine. Powderedpotassium hydroxide (1.57 g, 27.9 mmol) was added and the reactionmixture was stirred at rt overnight under nitrogen. Water (100 mL) wasadded, the solid was isolated by filtration and washed with water togive a yellow solid (1.83 g, 68%). The compound (1.78 g, 6.17 mmol) wassuspended in 15 mL glacial AcOH. Five drops of conc. HCl was added andthe reaction mixture was stirred at 110° C. for 2 h, then cooled to rt.Water (100 mL) was added. The formed solid was separated by filtration,washed with water and dried under vacuum to give2-(3-fluoro-4-methoxyphenyl)chromen-4-one as a white solid (1.62 g,97%). 2-(3-Fluoro-4-methoxyphenyl)chromen-4-one (1.6 g, 5.92 mmol) wassuspended in 40 mL of Hi. Glacial AcOH (15 mL) was added and thereaction mixture was stirred at 110° C. for 4 h, then cooled to rt.Water (200 mL) was added, and the solid was isolated by filtration,washed with water and dried under vacuum. The crude compound was washedwith 1:1 dichloromethane and methanol (15 mL) to give 1.1 g of2-(3-fluoro-4-hydroxyphenyl)chromen-4-one (72%) as a pale yellow solid.MS (ES) m/z: 257.91 (M+1), 256.88 (M); Mp. 275-276° C.

Example 13

2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid

To a solution of 2′-hydroxyacetophenone (5.43 g, 40 mmol) in cyclohexane(28 mL) was added dimethylcarbonate (28 mL). The mixture was stirredunder nitrogen and heated to 60° C. Chlorosulfonic acid was added over aperiod of 15 min. Liberated HCl was removed by trapping with solid NaOH.On completion of the addition, the reaction mixture was heated to 70° C.for 1 h and then cooled to rt. The solid was filtered off, washed with amixture of dimethyl carbonate and cyclohexane (1:1, 20 mL) and driedunder vacuum to give 3-acetyl-4-hydroxybenzene sulfonic acid as yellowsolid (4.5 g, 52%). 3-Acetyl-4-hydroxybenzene sulfonic acid (2.16 g, 10mmol) was suspended in 20 mL anhydrous pyridine. 4-Methoxybenzoylchloride (3.4 g, 20 mmol) was added slowly at rt. Stirring continuedunder nitrogen for 15 h. Excess pyridine was removed under reducedpressure. The solid obtained was dried under vacuum. This material wasused without further purification. This crude compound (˜10 mmol) wasdissolved in 10 mL anhydrous pyridine. Powdered KOH (2.8 g, 50 mmol) wasadded and the reaction mixture was stirred at rt for 14 h undernitrogen. Water (10 mL) was added and the mixture was concentrated todryness. The crude product was taken in 10 mL of glacial AcOH. Fivedrops of concentrated HCl was added and the reaction mixture was stirredat 110° C. for 4 h, then cooled to rt. The yellow solid was isolated byfiltration, washed with AcOH and dried under vacuum to give 2-(4-methoxyphenyl)-4-oxo-4H-chromen-6-sulfonic acid (0.475 g, 14%) as yellow solid.The product (0.375 g, 1.13 mmol) was suspended in HI (7 mL). GlacialAcOH (3 mL) was added and the reaction mixture was stirred at 110° C.for 2 h, then cooled to rt. The solid was isolated by filtration, washedwith AcOH and dried under vacuum. The crude compound was triturated withether to afford 2-(4-hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid(0.2 g, 55%) as yellow solid. MS (ES) m/z: 319.88 (M+1), 318.85 (M);¹³C-NMR (DMSO-d₆): δ 177.5, 163.7, 161.7, 156.1, 146.1, 132.1, 129.1,123.1, 122.3, 122.2, 118.7, 116.6, 105.5.

Example 14

6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxy-5′-acetoxyacetophenone (2.63 g, 13.54mmol), 4-acetoxymethyl benzoic acid (2.63 g, 13.54 mmol) and pyridine(20 mL). POCl₃ (2.07 g, 13.54 mmol) was added slowly on cooling. Thenthe reaction mixture was stirred for 24 h at rt under nitrogen. Thereaction mixture was poured into ice water and extracted with EtOAc. Theorganic layer was washed with water, dried and concentrated to giveproduct (3.0 g, 60%). A solution of this product (3.0 g, 8.10 mmol) inTHF (50 mL), was added potassium t-butoxide (1.187 g, 9.72 mmol) and thereaction mixture was stirred for 24 h at rt under N₂. The reactionmixture was poured into saturated aqueous solution of NH₄Cl. The organiclayer was separated, washed with water, dried and concentrated to givecrude diketone (3.0 g, 99%). The mentioned diketone (3.0 g, 8.10 mmol)was taken into a mixture of 48% HCl (2 mL) and AcOH (25 mL) and heatedat 100° C. for 1 h. The reaction mixture was cooled to rt, diluted withwater and extracted with EtOAc. The organic layer was washed with water,brine, dried and concentrated to give the di-acetyl flavone (1.2 g,74%). To a solution of the di-acetyl flavone (228 mg, 0.676 mmol) inmethanol:THF (5 ml:5 mL), K₂CO₃ (112 mg, 0.811 mmol) was added andstirred for 2 h at rt, then the reaction mixture was neutralized bydilute HCl and extracted with EtOAc. The combined organic layers werewashed with water, brine, dried and concentrated to give a crudeproduct, which was purified by column chromatography using 2% MeOH indichloromethane, to give 100 mg of6-hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one (50%). MS (ES) m/z:269.90 (M+1), 268.91 (M); Mp. 262-265° C.

Example 15

2-(2-Fluoro-4-hydroxyphenyl)chromen-4-one

To a solution of 2-fluoro-4-hydroxybenzoic acid (1.87 g, 12 mmol) in 30mL pyridine was added acetic anhydride (1.84 g, 18 mmol) and catalyticamount of DMAP and the reaction mixture was stirred at rt for 15 h. Thepyridine was removed under reduced pressure; the residue was dissolvedin EtOAc (100 mL), washed with 1N HCl (20 mL), water (20 mL) and driedover anhydrous Na₂SO₄. Removal of solvent gave 2-fluoro-4-acetoxybenzoicacid in 57% yield (1.35 g). To a suspension of 2-fluoro-4-acetoxybenzoicacid (1.33 g, 6.71 mmol) in 10 mL anhydrous dichloromethane was addedoxalyl chloride (2.56 g, 20.13 mmol). Two drops of DMF was added and thereaction mixture was stirred at rt for 3 h. The solvent and excessoxalyl chloride were removed under reduced pressure to give 1.48 g of2-fluoro-4-acetoxybenzoyl chloride which was used in next step withoutpurification. To a solution of 2′-hydroxyacetophenone (0.93 g, 6.83mmol) in 15 mL anhydrous pyridine was added 2-fluoro-4-acetoxybenzoylchloride (1.48 g, 6.83 mmol) and the reaction mixture was stirred at rtfor 15 h under nitrogen atmosphere. Then the reaction mixture was pouredinto 100 mL 2N HCl, extracted with EtOAc (200 mL). The crude compoundwas purified by column chromatography (Silica Gel 230-400 mesh; 20%EtOAc in hexanes as eluent) to give 4-acetoxy-2-fluorobenzoic acid2-acetyl phenyl ester (1.14 g, 53%). The ester compound (0.74 g, 2.34mmol) was dissolved in 10 mL anhydrous THF. Potassium tert-butoxide(0.53 g, 4.68 mmol) was added in portions and stirred at rt undernitrogen for 1 h. A yellow solid was formed. The reaction mixture wasquenched with 15 mL saturated aqueous ammonium chloride. EtOAc (100 mL)was added and the organic phase was separated and dried over anhydrousNa₂SO₄. Removal of solvent gave crude product (0.725 g) which was usedin next step without further purification. This crude compound (0.72 g,2.62 mmol) was dissolved in 10 mL glacial AcOH, conc. HCl (1 mL) wasadded and the reaction mixture was stirred at 110° C. for 4 h. Thereaction mixture was cooled to rt. The solid was isolated by filtration,washed with AcOH and dried under vacuum to give 126 mg (21%) over 2steps. MS (ES) m/z: 256.89 (M), 255.86 (M−1); Mp. 287-289° C.

Example 16

2-(4-Hydroxyphenyl)-8-nitro-4H-chromen-4-one

In a 250 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-hydroxy-3-nitro-acetophenone (1.0 g, 5.52 mmol),4-methoxybenzoyl chloride (0.94 g, 5.52 mmol) and pyridine (20 mL). Thereaction mixture was stirred for 24 h at rt under nitrogen. The reactionmixture was poured into ice-water and extracted with EtOAc. The organiclayer was washed with water, dried and concentrated to give crudeproduct (1.7 g, 99%). To a solution of the crude product (1.56 g, 4.95mmol) in THF (50 mL), was added potassium t-butoxide (666 mg, 5.94 mmol)and the reaction mixture was stirred for 16 h at rt under N₂. Thereaction mixture was poured into a saturated solution of NH₄Cl. Theorganic layer was separated, washed with water, dried and concentratedto give the crude diketone (1.5 g, 99%). The diketone (1.5 g, 4.76 mmol)was dissolved in a mixture of 48% HCl (1 mL) and AcOH (15 mL) and heatedat 100° C. for 1 h. The reaction mixture was cooled to rt, diluted withwater and extracted with EtOAc. The organic layer was washed with water,brine, dried and concentrated to give cyclized product, which waspurified by crystallization to give 760 mg of compound in 54% yield. Amixture of the cyclized compound (360 mg, 1.21 mmol) and pyridiniumhydrochloride (5 g) was heated at 190° C. for 3 h. The reaction mixturewas cooled to rt, diluted with water, neutralized with NaHCO₃ andfiltered to give crude product, which purified by chromatography using5% MeOH in dichloromethane to give 196 mg of2-(4-hydroxyphenyl)-8-nitro-4H-chromen-4-one (57%). MS (ES) m/z: 284.88(M+1), 283.88 (M); Mp. 299-301° C.

Example 17

2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one

In a 250 mL dry flask was charged with 2-hydroxy-3-methoxybenzoic acid(6.0 g, 36.0 mmol) and anhydrous THF (20 mL) under N₂. Methyl lithium inan ether solution (1.6 M, 73.5 mL, 117.6 mmol) was added dropwise over20 min. The reaction mixture was heated to reflux for 20 h. Aftercooling the mixture was poured into 25 mL of brine with 6 N HCl andextracted with 100 mL of EtOAc. The organic layer was further washedwith brine three times and dried over sodium sulfate. The solvent wasevaporated and the residue was purified by column (hexane:EtOAc 2.5:1)to give 1-(2-hydroxy-3-methoxy-phenyl)-ethanone (4.3, 71.8%).1-(2-Hydroxy-3-methoxy-phenyl)-ethanone (1.0 g, 6.0 mmol),4-acetoxybenzoic acid (1.08 g, 6.0 mmol) and phosphorus oxychloride(0.923 g, 6.0 mmol) in 10 mL pyridine were stirred at rt overnight. Thereaction mixture was poured into water (100 mL) and the isolated solidwas washed with water. The solid was dissolved in dichloromethane andpurified by column chromatography (hexane:EtOAc 2:1) to give theintermediate (1.05 g, 53.13%). Potassium tert-butoxide (0.4 g, 3.5 mmol)was added to this intermediate (1.05 g, 3.2 mmol) in 20 mL anhydrousTHF. The reaction mixture was stirred for 4 h at rt. The mixture waspoured into water (100 mL) with 1 mL AcOH (adjusted pH to 6-7.0). Thesolid was further rinsed with water and dissolved in dichloromethane.The organic layer was wash with brine and dried over sodium sulfate. Thecrude compound was treated with AcOH and two drops of concentrated HClsolution and heated to 110° C. for 1 h. The AcOH was evaporated and thesolid residue was dissolved in MeOH and potassium carbonate (3.8 mmol)was added. The reaction mixture was stirred for 1 hour at rt. Thereaction mixture was neutralized with AcOH and the solvent wasevaporated. The residue was poured into water and the solid wascollected by filtration and purified by column to give 150 mg of2-(4-hydroxyphenyl)-8-methoxy-4H-chromen-4-one (17.4%). MS (ES) m/z:269.93 (M+1), 268.91 (M); Mp. 281-283° C.

Example 18

2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one

To a solution of 4′,6′-dimethoxy-2′-hydroxy acetophenone (1.96 g, 10mmol) in 20 mL anhydrous pyridine was added 4-acetoxy benzoic acid (2.16g, 12 mmol). The mixture was cooled to 0° C. and phosphorous oxychloride(1 mL) was added. A white precipitate was formed. The reaction mixturewas stirred at rt for 2 h under nitrogen atmosphere. The reactionmixture was poured into 100 mL cold 2 N HCl. The mixture was extractedwith EtOAc (2×200 mL). The combined organic layers were washed withwater and brine and dried over anhydrous Na₂SO₄. The solvent was removedunder vacuum to give a gummy solid product (3.36 g, 94%), which was usedin next step without further purification. The gummy product (3.35 g,9.35 mmol) was dissolved in 30 mL anhydrous THF. Potassium tert-butoxide(2.1 g, 18.7 mmol) was added in portions and the mixture was stirred atrt under nitrogen for 15 h. A yellow solid was formed. The reaction wasquenched with saturated aqueous ammonium chloride solution (30 mL).EtOAc (100 mL) was added and the organic layer was separated and driedover anhydrous Na₂SO₄. Removal of solvent gave fluffy solid (2.52 g)which was used in next step without further purification. The fluffysolid (1.0 g, 2.79 mmol) was dissolved in glacial AcOH (8 mL).Concentrated HCl (5 drops) was added and the reaction mixture wasstirred at 110° C. for 2.5 h. The mixture was cooled to rt and water (50mL) was added. The solid was filtered off, washed with water and driedunder vacuum. The crude compound was purified by column chromatography(Silica Gel 230-400 mesh; 30% EtOAc in hexanes as eluent) to give 204 mgof 2-(4-hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one (25%) as anoff-white solid. MS (ES) m/z: 299.94 (M+1), 298.93 (M); Mp. 301-303° C.

Example 19

2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-one

To a solution of 3-bromo-4-hydroxy-benzoic acid (3.0 g, 13.83 mmol) indichloromethane (100 mL) and pyridine (20 mL) was added acetyl chloride(1.1 mL, 15.20 mmol) and the resulting mixture was stirred at rt for 1h. The reaction was quenched with water (50 mL) and acidified with HCl(1 N) to adjust pH=1˜2. The mixture was extracted with dichloromethane(3×100 mL) and concentrated to afford 4-acetoxy-3-bromo-benzoic acid(3.6 g, 100%). To a solution of 4-acetoxy-3-bromo-benzoic acid (3.60 g,13.83 mmol) in dichloromethane (100 mL) at rt was added oxalyl chloride(1.8 mL, 20.75 mmol) and DMF (0.5 mL), sequentially. The resultingmixture was stirred at rt for 1 h. The mixture was concentrated toafford the acid chloride. To a solution of the freshly prepared acidchloride in dichloromethane (100 mL) were added 2′-hydroxyacetophenone(2.5 mL, 20.75 mmol) and triethylamine (3.9 mL, 27.66 mmol). Thismixture was stirred at rt for 2 h. The reaction was quenched with water(100 mL) and extract with dichloromethane (3×150 mL). The combinedorganic layers were concentration to afford an oily residue, which waspurified by column chromatography using 30% EtOAc in hexane to give thephenol ester (4.5 g, 86%). A solution of the phenol ester (4.0 g, 10.61mmol) in THF (100 mL) was mixed with potassium t-butoxide (1.6 g, 14.32mmol) and stirred at 60° C. for 1.5 h. This mixture was cooled to rt,diluted with water (100 mL) and acidified with HCl (1 N) to adjustpH=5-6. The mixture was extract with dichloromethane (3×100 mL) and thecombined organic layers were concentration to give a yellow solidresidue. The residue was purified by column chromatography using 30%EtOAc in hexane to give the diketone (2.3 g, 58%). A solution of thediketone (1.50 g, 3.98 mmol) in AcOH (100 mL) and HCl (conc., 2 mL) wasstirred at reflux for 16 h. This mixture was cooled to rt, diluted withwater (100 mL), extracted with dichloromethane (3×100 mL) andconcentrated. The residue was purified by column chromatography using50% EtOAc in hexane to give the flavone acetate (0.4 g, 28%). A solutionof the flavone acetate (0.53 g, 1.48 mmol) in MeOH (80 mL) and water (20mL) was mixed with potassium carbonate (1.10 g, 8.00 mmol) and wasstirred at rt for 1 h. The solid was filtered off, washed with water,hexanes, and dichloromethane sequentially to give 390 mg of product(83%) as a light yellow solid. MS (ES) m/z: 318.84+316.84 (two isotopesof M); Mp. 273.5-274.9° C.

Example 20

3-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-onehydrochloride

A 100 mL dry flask was charged with 2′-hydroxy propiophenone (10.0 g, 67mmol), 4-acetoxybenzoic acid (12.0 g, 67 mmol), phosphorus oxychloride(6.7 mL, 73 mmol), pyridine (25 mL) and anhydrous dichloromethane (10mL) sequentially. The reaction mixture was stirred at rt for 3 h thenpoured into 150 mL of cold water. EtOAc (3×100 mL) was used to extractthe compound out of the aqueous layer. The combined organic layers werewashed with sodium bicarbonate, brine and dried over sodium sulfate. Theresidue was purified by column chromatography (hexane:EtOAc 2:1) toafford 14.6 g of the corresponding phenol ester (77%). To a solution ofthe phenol ester (14.0 g, 51.5 mmol) in THF (200 mL) was added potassiumtert-butoxide (8.64 g, 77.2 mmol) and the reaction mixture was stirredat rt for 16 h. The reaction was quenched by adding water (100 mL), thenextracted with dichloromethane (3×100 mL). The combined organic layerswere concentrated to afford a solid residue. This residue was dissolvedin AcOH (160 mL) and concentrated HCl (5 mL) and the mixture was stirredat reflux for 8 h. The reaction was quenched by adding water (100 mL).The reaction mixture was extracted with dichloromethane (3×100 mL) andconcentrated to afford a solid residue. This solid was re-dissolved inMeOH (200 mL) and water (200 mL) and the solution was mixed withpotassium carbonate (16 g) and stirred at rt for 2 h. The MeOH wasremoved and the aqueous layer was acidified with HCl (1 N) to pH=5. Thesolid was filtered off and further washed with water, EtOAc anddichloromethane to afford the flavone analog (7.5 g, 58% over two step).A solution of the flavone (6.9 g, 27.4 mmol) in acetic anhydride (50 mL)was stirred at reflux for 16 h. The mixture was cooled to rt and pouredinto ice water (300 mL). The mixture was extracted with dichloromethane(3×100 mL) and concentrated to afford a light yellow solid as thecorresponding flavone acetate (6.8 g, 84%). To a solution of the flavoneacetate (6.8 g, 23.1 mmol) in carbon tetrachloride (200 mL) at refluxwas added NBS (4.12 g, 23.1 mmol) and benzoyl peroxide (0.56 g, 2.31mmol). The reaction was stirred at reflux for 4 h and then quenched withHCl (0.5 N, 100 mL). The reaction mixture was extracted withdichloromethane (3×100 mL) and the combined organic layers wereconcentrated to afford3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one as a light yellowcompound (8.6 g, 100%).

A solution of3-((dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-onehydrochloride (0.3 g, 0.8 mmol) in DMF (20 mL) was mixed withdimethylamine solution in THF (2 mL, 4 mmol) and was stirred at 45° C.for 24 h. The reaction mixture was extract with EtOAc (3×100 mL) andconcentrated to an oily residue. This residue was re-dissolved in MeOH(50 mL) and water (50 mL), mixed with potassium carbonate (1 g), andstirred at rt for 0.5 h. The mixture was extracted with dichloromethane(3×50 mL) and concentrated to afford an oil. This oil was re-dissolvedin dichloromethane (10 mL) and mixed with HCl in ether (10 mL, 20 mmol)and stirred at rt for 1 h. The resulting solid was filtered and washedwith dichloromethane and hexanes to give3-((dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-onehydrochloride a light yellow solid product (0.24 g, 90%). MS (ES) m/z:295.98 (M); Mp. 271.5-272.3° C.

Example 21

2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile

A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.3 g,0.8 mmol) in DMF (15 mL), water (15 mL), and NaCN (0.12 g, 2.4 mmol) wasstirred at 45° C. for 24 h. The reaction mixture was extracted withEtOAc (3×100 mL) and concentrated to afford a solid residue. Thisresidue was re-dissolved in MeOH (50 mL) and water (50 mL) and was mixedwith potassium carbonate (1 g) and stirred at rt for 0.5 h. MeOH wasremoved, the aqueous layer was acidified with HCl (1 N) to pH=5. Thesolid was filtered off and then purified by column chromatography(hexane:EtOAc 1:2). The resulting solid was re-crystallized fromdichloromethane and hexanes to give2-(2-(4-hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile as a lightyellow solid product (0.14 g, 63%). MS (ES) m/z: 278.94 (M+1), 277.93(M); Mp. 258.2-259.5° C.

Example 22

3-(Hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one

A solution of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.50g, 1.5 mmol) and sodium acetate (1.24 g, 15.0 mmol) in ACOH (20 mL) washeated to reflux for 15 h. AcOH was removed and the residue was pouredinto water and extracted with EtOAc (100 mL). The organic phase wasfurther washed with brine and dried over sodium sulfate. The residue wasmixed with potassium carbonate (0.52 g) and MeOH (10 mL) and stirred for2 h. AcOH (1.0 mL) was added and MeOH was removed. The residue waspoured into water and the solid was washed additionally with water andhexane to give 3-(hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one(0.265 g, 62.6%). MS (ES) m/z: 269.94 (M+1), 268.94 (M); Mp. 234-235° C.

Example 23

2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile

2-Acetyl-4-cyanophenol (0.78 g, 4.84 mmol), 4-acetoxybenzoic acid (0.872g, 4.84 mmol) and phosphorus oxychloride (0.5 mL) and pyridine (2.0 mL)were mixed in anhydrous dichloromethane (10 mL). The reaction mixturewas stirred overnight at rt and then poured into cold water andextracted with dichloromethane (150 mL). The organic layer was washedwith sodium bicarbonate, brine and dried over sodium sulfate followed byconcentration. The crude compound (1.40 g, 89.5%) was obtained afterevaporation of the solvent. The crude compound (1.4 g, 4.33 mmol) wasdissolved into dry THF (20 mL) and potassium tert-butoxide (0.51 g, 4.55mmol) was added and the reaction mixture was stirred at rt for 2 h. Thesolvent was removed, followed by addition of water (50 mL) and EtOAc(150 mL) was used to extract out the compound. The organic layer waswashed with brine and dried over sodium sulfate. The crude product (1.20g) and 4 drops of sulfuric acid were added to AcOH (15 mL). The reactionmixture was heated to 110° C. for 1 h. AcOH was removed and sodiumbicarbonate solution was added followed by extraction with EtOAc. Theorganic layer was washed with brine and dried over sodium sulfate andconcentrated. The crude and potassium carbonate (1.1 g) was added toMeOH (20 mL). The reaction mixture was stirred for 2 h. AcOH (1.0 mL)was added and MeOH was removed. The residue was purified by preparativeHPLC to give 70 mg of2-(4-hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile. MS (ES) m/z:264.91 (M+1), 263.90 (M); Mp. 296-298° C.

Example 24

2-(4-Hydroxyphenyl)-3-methyl-4H-chromen-4-one

A 100 mL dry flask was charged with 2′-hydroxy propiophenone (10.0 g,0.067 mol), 4-acetoxybenzoic acid (12.0 g, 0.067 mol), POCl₃ (6.7 mL,0.073 mol), pyridine (25 mL) and anhydrous dichloromethane (10 mL). Thereaction mixture was kept at rt with stirring for 3 hours then pouredinto 150 mL of cold water. The mixture was extracted with EtOAc (150 mL)and the organic layer was washed with sodium bicarbonate, brine anddried over sodium sulfate. The crude compound was purified by columnchromatography (hexane:EtOAc 2:1) to give the intermediate (14.6 g,70.2%). The intermediate (14.0 g, 44.8 mmol) was dissolved in dry THF(150 mL) and potassium tert-butoxide (5.28 g, 47.0 mmol) was added. Thereaction mixture was stirred at rt for 2 h. The mixture was concentratedand water (50 mL) was added, followed by extraction with EtOAc (150 mL).The organic layer was washed with brine and dried over sodium sulfate.The crude compound (11.0 g, 35.2 mmol) was dissolved into AcOH (30 mL)and 37% HCl (2.0 mL) was added. The reaction was carried out at 110° C.for 2 h. AcOH was removed and 7.0 g potassium carbonate and 40 mLmethanol were added followed by stirring overnight. AcOH (5.0 mL) wasadded to the mixture and methanol was removed. Water (50 mL) was addedto the residue. The mixture was stirred for a while to obtain the solid,which was filtered off and further washed with water and EtOAc to give3.70 g of 2-(4-hydroxyphenyl)-3-methyl-4H-chromen-4-one (41.7%). MS (ES)m/z: 253.89 (M+1), 252.90 (M); Mp. 241-242° C.

Example 25

4-(6-Bromo-8-nitro-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate

To a solution of 2′-hydroxy-5′-bromoacetophonone (10 g, 46.5 mmol) incarbon tetrachloride (60 mL) at reflux was added 70% nitric acid (5.2mL, 79.6 mmol). The reaction mixture was stirred at reflux for 40 min.and then cooled to rt. The resulting solid was filtered off and washedwith water and hexanes to provide2′-hydroxy-3′-nitro-5′-bromoacetophonone (10.19 g, 84%). To a solutionof 3-fluoro-4-hydroxybenzoic acid (3.0 g, 19.2 mmol) in pyridine (20 mL)and dichloromethane (50 mL) was added acetyl chloride (1.8 mL, 25 mmol)and the reaction mixture was stirred at rt for 1 h. The reaction mixturewas washed with HCl (1 N, 2×100 mL), and concentrated to afford3-fluoro-4-acetoxybenzoic acid (3.18 g, 83%). To a solution of3-fluoro-4-acetoxybenzoic acid (3.18 g, 16.1 mmol) in dichloromethane(100 mL) was added oxalyl chloride (2.1 mL, 24.0 mmol) and DMF (0.2 mL)sequentially. The resulting mixture was stirred at rt for 1 h and thenconcentrated to afford the corresponding acid chloride. A mixture of theacid chloride, 2′-hydroxy-3′-nitro-5′-bromoacetophonone (4.17 g, 16.1mmol) and triethylamine (8.9 mL, 64.2 mmol) in dichloromethane (100 mL)was stirred at rt for 1 h and then concentrated. The residue wasre-dissolved in THF (100 mL) and mixed with potassium tert-butoxide (4.0g, 35.3 mmol). The reaction was stirred at rt for 16 h and then quenchedby adding water (100 mL). The mixture was extracted with dichloromethane(3×100 mL) and concentration to afford the crude diketone as a yellowsolid. This solid was re-dissolved in AcOH (100 mL) and HCl (conc., 5mL) and the mixture was stirred at reflux for 20 h. The reaction wasquenched with water (100 mL), extracted with dichloromethane (3×100 mL)and concentrated. A solution of the resulting residue in MeOH (50 mL)and water (50 mL) was mixed with potassium carbonate (2 g) and stirredat rt for 2 h. MeOH was removed and the aqueous layer was acidified withHCl (1 N) to pH=5. The solid was filtered off and washed with water,acetone, and dichloromethane sequentially to provide a solid of theflavone analog (1.85 g, 30% five steps combined). To a solution of theflavone analog (1.85 g, 4.87 mmol) in pyridine (50 mL) anddichloromethane (100 mL) at rt was added acetyl chloride (1.1 mL, 14.6mmol) and the reaction mixture was stirred at rt for 16 h. The reactionmixture was washed with HCl (1 N, 2×100 mL), and concentrated to afforda solid residue, which was purified by column chromatography(hexane:EtOAc 2:1). The resulting solid was re-crystallized from EtOAcand hexanes to afford4-(6-bromo-8-nitro-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate (1.1 g,54%) as a light yellow solid. MS (ES) m/z: 423.78, 421.77; Mp.236.2-238.5° C.

Example 26

2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one

A mixture of 3-bromomethyl-2-(4-hydroxyphenyl)-4H-chromen-4-one (0.52 g,1.57 mmol), sodium methoxide (1.36 mL, 6.28 mmol, 25% in MeOH) andanhydrous MeOH (10 mL) was stirred overnight at rt. The reaction mixturewas neutralized by addition of AcOH and the solvent was removed. Theresidue was poured into water and the solid was collected and purifiedby column chromatography (hexane:EtOAc 2:1) to give 155 mg of2-(4-hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one (35.0%). MS (ES)m/z: 283.95 (M+1), 282.93 (M); Mp. 237-239° C.

Example 27

8-Amino-2-(3-fluoro-4-hydroxyphenyl)-4H-chromen-4-one hydrochloride

A Parr Bottle charged with a solution of4-(6-bromo-8-nitro-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate (0.8 g,1.90 mmol) in THF (350 mL) and palladium carbon (10% on carbon, 0.2 g)was subjected for hydrogenation at 50 psi at rt for 16 h. The reactionmixture was passed through a Celite pad and the filtrate wasconcentrated. The resulting solid was filtered off and washed withdichloromethane to afford the aminoflavone analog as a brown solid (0.5g, 85%). A solution of the aminoflavone analog (0.5 g, 1.60 mmol) inMeOH (50 mL) and water (20 mL) was mixed with potassium carbonate (1 g)and stirred at rt for 1 h. The MeOH was removed and the aqueous layerwas neutralized with HCl (1 N). The resulting solid was filtered off,washed with MeOH, dichloromethane, and hexanes sequentially to providethe hydrolyzed product (0.204 g, 48%). To a solution of the hydrolyzedanalog (0.106 g, 0.391 mmol) in MeOH (20 mL) was added HCl ethersolution (5 mL, 10 mmol) and the reaction mixture was stirred at rt for1 h. The MeOH was removed, and the resulting solid was filtered off andwashed with a mixture of MeOH-dichloromethane (10:1) to afford 82 mg of8-amino-2-(3-fluoro-4-hydroxyphenyl)-4H-chromen-4-one hydrochloride(68%). MS (ES) m/z: 271.97; Mp. 256.4-258.5° C.

Example 28

6-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one

Dimethylamine (1M solution in THF, 1.2 mL) was added to6-bromomethyl-2-(4-hydroxyphenyl)chromen-4-one (206 mg, 0.62 mmol)dissolved in dry THF (10 mL). The reaction mixture was stirred at rt for17 hr. Most of the solvent was then removed in vacuo and the yellowishresidue was suspended in 20 mL of water. The resulting suspension wasstirred at rt for 30 min and the solid was removed by filtration, washedwith water, ether, and air-dried to afford6-((dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one (125 mg,68%). MS (ES) m/z: 296.98 (M+1), 295.97 (M); Mp. 99-102° C.

Example 29

2-(1-Oxy-pyridin-4-yl)-chromen-4-one

To a solution of 2-pyridin-4-yl-chromen-4-one (0.3 g, 1.35 mmol) in 15mL anhydrous dichloromethane was added m-chloroperbenzoic acid (57-86%)(0.33 g, 1.35 mmol) at 0° C. and the mixture was stirred for 10 min.under nitrogen. The ice-bath was removed and the stirring was continuedat rt for 4 h. A white precipitate was formed. The reaction mixture wasdiluted with dichloromethane (50 mL) and washed with 0.5 N aq. NaOHsolution (12 mL). The organic layer was dried over anhydrous Na₂SO₄. Thesolvent was removed and triturated with ether to afford2-(1-oxy-pyridin-4-yl)-chromen-4-one (0.27 g, 84%). MS (ES) m/z: 239.89(M); Mp. 258-259° C.

Example 30

2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-c]pyridine 7-oxide

A mixture of 2-(4-hydroxyphenyl)-pyrano[2,3-c]pyridin-4-one (0.50 g,2.09 mmol), acetyl chloride (0.164 g, 2.09 mmol) and anhydrous pyridine(2.5 mL) was stirred at rt overnight. The mixture was then poured intowater (100 mL) and stirred for 30 min. The solid was filtered andfurther washed with water and dry to give the ester (0.586 g, 99%). Theester (0.230 g, 0.82 mmol) and 3-chloroperoxybenzoic acid (0.242 g, 0.98mmol) were added to dichloromethane (10 mL) and the reaction mixture wasstirred at rt for 2 weeks. The mixture was concentrated and potassiumcarbonate (0.60 g) and MeOH (10 mL) was added and the reaction mixturewas stirred for 1 h. AcOH was added to adjust pH to 6.0-7.0, and thesolvent was removed. The residue was poured into water. The solid wascollected by filtration and washed with EtOAc to give 120 mg (57.4%) of2-(4-hydroxyphenyl)-4-oxo-4H-pyrano[2,3-c]pyridine 7-oxide. MS (ES) m/z:255.90 (M); Mp. 307-308° C.

Example 31

2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-b]pyridine 8-oxide

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.5g, 6.27 mmol), Ac₂O (700 mg, 6.89 mmol) and a catalytic amount of DMAP(50 mg) in pyridine (10 mL) and the reaction mixture was stirred for 16h at rt. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer washed with water, dried andconcentrated to give a 2-(4-acetoxyphenyl)-pyrano[2,3-b]pyridin-4-one(930 mg, 53%).

To a stirred solution of the 4-acetoxy compound (930 mg, 3.30 mmol) inCH₂Cl₂ (50 mL), mCPBA (1.9 g, 11.3 mmol) was added and the reactionmixture was stirred at rt for 5 days. The reaction mixture was dilutedwith CH₂Cl₂ and washed with NaHCO₃ solution. The organic layer wasseparated, washed with water, brine, dried and concentrated to givecrude product, which was purified by column chromatography, using 5%methanol in CH₂Cl₂ to give 168 mg of N-oxide product in 17% yield. To asolution of the acetoxy N-oxide (168 mg, 0.565 mmol) in methanol:THF (10mL:10 mL), K₂CO₃ (156 mg, 1.13 mmol) was added and the mixture wasstirred for 2 h at rt. The reaction mixture was neutralized by diluteHCl. The solid was isolated by filtration, washed with water and driedto give 2-(4-hydroxyphenyl)-4-oxo-4H-pyrano[2,3-b]pyridine 8-oxide (150mg, 100%). MS (ES) m/z: 255.90 (M); Mp. 314-315° C.

Example 32

2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[3,2-c]pyridine 6-oxide

A solution of 2-(4-hydroxyphenyl)-pyrano[3,2-c]pyridin-4-one (1.75 g,7.32 mmol) in acetic anhydride (50 mL) was stirred at reflux for 16 h.The reaction mixture was cooled to rt, quenched with water (100 mL),extracted with CH₂Cl₂ (3×100 mL). The combined organic layers wereconcentrated. The resulting residue was purified by columnchromatography (hexane:ethyl acetate 1:1 to 1:3) to provide 1.3 g of thecorresponding acetate (63%). A solution of the acetate (0.4 g, 1.42mmol) and mCPBA (1.0 g, 4.70 mmol) in CH₂Cl₂ (50 mL) was stirred at rtfor 11 days. The CH₂Cl₂ was removed by concentration. The residue wasre-dissolved in MeOH (150 mL) and water (120 mL) and was mixed withpotassium carbonate (1.0 g). The mixture was stirred at rt for 1 hourand neutralized with HCl (1 N). The resulting solid was filtered off,washed with water, MeOH, and CH₂Cl₂ sequentially to afford a lightyellow solid of 2-(4-hydroxyphenyl)-4-oxo-4H-pyrano[3,2-c]pyridine6-oxide (0.21 g, 58%). MS (ES) m/z: 255.96 (M); 322.8-323.4° C.

Example 33

2-(3-Fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-chromen-4-one

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-hydroxy-5-methoxymethyl acetophenone (1.62 g,9.014 mmol), 4-methoxy-3-fluoro benzoyl chloride (1.7 g, 9.014 mmol) andpyridine (20 mL). The reaction mixture was stirred for 16 h at rt undernitrogen. The reaction mixture was poured into ice-water. The solidswere filtered off, washed with water and dried to give the intermediate(2.33 g, 78%). To a solution of this intermediate (2.33 g, 7.01 m mol)in THF (50 mL), was added potassium t-butoxide (945 mg, 8.42 mmol) andthe reaction mixture was stirred for 16 h at rt under N₂. The reactionmixture was poured into saturated solution of NH₄Cl. The organic layerwas separated, washed with water, dried and concentrated to give crudeintermediate diketone (2.3 g, 98.7%). The diketone compound (2.3 g, 6.92mmol) was taken into a mixture of HCl (1 mL) and acetic acid (15 mL) andheated at 100° C. for 1 h. The reaction mixture was cooled to rt,diluted with water and extracted with ethyl acetate. The organic layerwas washed with water, brine, dried and concentrated to give 1.75 g ofthe intermediate in 80.6% yield. In a 100 mL dry round-bottomed flaskfitted with condenser and magnetic stirrer were placed this intermediate(925 mg, 2.94 mmol) in CH₂Cl₂ (30 mL). BBr₃ (2.21 g, 8.83 mmol, 1Msolution in CH₂Cl₂) was added slowly at 0° C. The reaction mixture wasstirred for 16 h at rt under nitrogen. The reaction mixture was quenchedby carefully adding methanol. The solvent was removed under reducedpressure and the resulting solid was washed with water and dried to give1.0 g of crude 3′-fluoro-4′-methoxy-5-bromo methyl flavone in 97% yield.To a solution of 5-bromomethyl flavone (1.0 g, 2.86 mmol) in DMF (20mL), potassium acetate (845 mg, 8.60 mmol) was added. The mixture washeated at 100° C. for 1 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined organic layers werewashed with water, brine, dried over Na₂SO₄ and concentrated to givecrude acetyl flavone (810 mg, 86%). To a solution of the acetyl flavone(810 mg, 2.47 mmol) in methanol (15 mL), K₂CO₃ (1.02 g, 7.41 mmol) wasadded and the reaction mixture was stirred for 2 h at rt. The solventwas removed and the product was taken in to water and neutralized bydilute HCl. The solid was separated by filtration, washed with water anddried to give2-(3-fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-chromen-4-one in 38%yield. MS (ES) m/z: 286.96 (M); Mp. 256-258° C.

Example 34

2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one

In a 500 mL dry round bottom flask with reflux condenser and magneticstirrer was placed with 2-chloro-3-ethyl nicotinate (40.0 g, 215.5 mmol)in methanol (200 mL). CH₃ONa in methanol (25%, 65 mL, 301.7 mmol) wasadded slowly and the reaction mixture was refluxed for 16 h. Thereaction was cooled to rt, quenched by addition of a saturated aqueousNH₄Cl solution. The aqueous mixture was extracted with ethyl acetate.The combined organic layers were washed well with water, brine, driedover Na₂SO₄ and concentrated to give 35 g of 2-methoxy-3-methylnicotinate with 97% yield. Sodium hydride (60% in oil, 9.21 g, 230.3mmol) was added to a dry 500 mL round bottom flask followed by 100 mLDMF. 4-Methoxyacetophenone (31.45 g, 209.44 mmol) in 50 mL dry DMF wasadded dropwise at 0° C. over 30 min. The reaction mixture was stirredfor 1 h at rt. 2-Methoxynicotinic acid methyl ester (35 g, 209.44 mmol)was dissolved in 50 mL dry DMF and added slowly, keeping the temperatureat 0° C. The mixture was stirred for 16 h at rt, then quenched byaddition of a saturated aqueous NH₄Cl solution and diluted with water.The solid was filtered off, washed with water and dried to give 56.7 gdiketo product in 95% yield.

The diketo compound (56.7 g, 198.9 mmol) was added to a 1 L round bottomflask together with pyridinium hydrochloride (345 g). The mixture washeated at 190° C. for 5 h. The reaction mixture was cooled to rt anddiluted with water. The solid was isolated by filtration and purified bycolumn chromatography using 5% methanol in CH₂Cl₂ to give2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (23.25 g, 48.8%). MS(ES) m/z: 240.07 (M+1); ¹³C-NMR (DMSO-d₆): δ 178.2, 164.2, 161.8, 160.8,153.9, 136.3, 129.2, 123.2, 121.8, 116.8, 116.75, 116.74, 105.7.

Example 35

2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one

In a 500 mL round-bottom flask fitted with condenser and magneticstirrer were placed MeOH (250 mL), 3-hydroxypyridine-2-carboxylic acid(10.0 g, 71.9 mmol) and concentrated H₂SO₄ (3 mL). The reaction mixturewas heated at 64° C. for 24 hs. The reaction mixture was cooled to rt.The solvent was removed under reduced pressure; the residue waspartitioned between EtOAc (150 mL) and water (20 mL). Solid sodiumcarbonate was added to adjust pH to 6. The organic layer was separated,dried over Na₂SO₄, concentrated to give 3.5 g of crude3-hydroxypyridine-2-carboxylic acid methyl ester (32%).

In a 50 mL round-bottom flask fitted with magnetic stirrer were placed3-hydroxypyridine-2-carboxylic acid methyl ester (3.5 g, 22.80 mmol),K₂CO₃ (3.46 g, 25.0 mmol), MeI (4.87 g, 34.3 mmol) and DMF (20 mL). Thereaction mixture was stirred for 18 h at rt under nitrogen. The reactionmixture was diluted with EtOAc (30 mL) and water (10 mL). The organiclayer was separated and aqueous layer was extracted with EtOAc. Thecombined organic extracts were dried over Na₂SO₄ and concentrated togive the crude product. The crude product was purified by columnchromatography using 30% EtOAc in hexane to give 2.1 g of3-methoxypyridine-2-carboxylic acid methyl ester (54%).

In 100 mL round-bottom flask fitted with magnetic stirrer were placedthe NaH (1.62 g of 60% suspension in mineral oil, 40 mmol) and thesolution of t3-methoxypyridine-2-carboxylic acid methyl ester (3.5 g, 20mmol) in anhydrous DMF (20 mL). The mixture was stirred for 15 min at rtunder N₂, then the solution of 4-methoxyacetophenone (3.3 g, 22 mmol)was added via syringe. The reaction mixture was stirred overnight at rt,then 10% aqueous solution of NaHSO₄ was used to adjust pH to 7. Theorganic layer was separated and aqueous layer was extracted with EtOAc.The combined organic extracts were dried over Na₂SO₄ and concentrated togive the crude product. The crude product was purified by columnchromatography using 30% EtOAc in hexane to give 4.68 g of1-(4-methoxyphenyl)-3-(3-methoxypyridin-2-yl) propane-1,3-dione (80%).

In 50 mL round-bottom flask fitted with magnetic stirrer were placed1-(4-methoxyphenyl)-3-(3-methoxypyridin-2-yl) propane-1,3-dione (4.68 g,16 mmol) and 45% aqueous solution of HBr (25 mL). The reaction mixturewas refluxed for 3 h, then cooled down to rt. Solid NaHCO₃ was used toadjust pH to 7, followed by EtOAc (30 mL). The organic layer wasseparated and aqueous layer was extracted with EtOAc (2×30 mL). Thecombined organic extracts were dried over Na₂SO₄, concentrated to givethe crude product, which was purified by column chromatography using 30%MeOH in EtOAc to give 125 mg of2-(4-hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one (3.2%). MS (ES) m/z:240.09 (M+1), and 149.06.

Example 36

2-(4-Hydroxyphenyl)-pyrano[2,3-c]pyridin-4-one

A 50 mL flask was charged with 5.0 g (0.0354 mol) 3-fluoroisonicotinicacid and thionyl chloride (3.88 mL, 0.053 mol). The mixture was heatedto reflux for 1 h, then the excess thionyl chloride was evaporated undervacuum. Anhydrous methanol was added to the residue and the mixture washeated to reflux for one hour. The reaction mixture was poured intosodium bicarbonate solution and pH was adjusted to 7.0. The mixture wasextracted with EtOAc and the organic layer was dry over sodium sulfate.The organic solvent was evaporated yielding the product (4.80 g, 88%). A50 mL dry flask was charged with methyl 3-fluoroisonicotinitate (3.50 g,0.0227 mol), 4-methoxyacetophenone (3.60 g, 0.024 mol) and 10 mL dry DMFunder nitrogen. Sodium hydride (1.82 g, 60% in oil) was added and thereaction was stirred for 30 min, then poured into ammonium chloridesolution and extracted with EtOAc and dried over sodium sulfate. Thesolution was concentrated and the residue was pass through a column(EtOAc:hexane 1:3) to give the product (3.50 g, 54.0%). A 50 mL flaskwas charged with this product (0.5 g, 1.75 mmol) and pyridine hydrogenchloride (2.02 g, 17.5 mmol) and heat to 190° C. for 4 h. The mixturewas poured into a sodium bicarbonate solution and the solid wascollected by filtration, washed with EtOAc and methanol to give2-(4-hydroxyphenyl)-pyrano[2,3-c]pyridin-4-one as a yellow product (0.36g, 86%). MS (ES) m/z: 240.90 (M+1), 239.89 (M); Mp. 294-296° C.

Example 37

2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one

Methyl 2-methoxynicotinate was synthesized from ethyl 2-chloronicotinatewith sodium methoxide as in Example 34. A 50 mL flask was charged withmethyl 2-methoxynicotinate (2.50 g, 0.015 mol), 10 mL dry DMF and 60%NaH (0.745 g, 0.0186 mol) with magnetic stirring.3′-Fluoro-4′-methoxyacetophenone (2.60 g, 0.0155 mol) in 6 mL anhydrousDMF was added over 5-10 min. After addition, the reaction mixture wasstirred for 30 min. The mixture was poured into 50 mL NH₄Cl solution,the yellow solid was filtered and further washed with water and purifiedby column chromatography (hexane:EtOAc 4:1) to get (3.0 g, 66.4%) ofproduct. A 50 mL flask was charged with this product (0.8 g, 2.64 mmol)and pyridine hydrogen chloride (3.04 g, 26.4 mmol) and heated to 190° C.for 4 h. The mixture was poured into sodium bicarbonate solution and thesolid was collected by filtration, washed with EtOAc and MeOH and passedthrough a column (methanol:dichloromethane 1:4) to afford 400 mg of2-(3-fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one (59%). MS (ES)m/z: 257.85 (M); Mp. 267-268° C.

Example 38

2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one

Methyl 2-methoxynicotinate was synthesized from ethyl 2-chloronicotinatewith sodium methoxide as described in Example 34. A 100 mL dry flask wascharged with 2-methylanisole (7.92 g, 65 mmol), acetyl chloride (5.1 mL,71 mmol), aluminum chloride (9.45 g, 71 mmol) and 40 mL of anhydrousdichloromethane. The reaction mixture was kept at reflux for 2 h, thenpoured into 15 mL of HCl (3 N) and extracted with 100 mL ether. Theorganic layer was further washed with sodium bicarbonate to pH 6-7, thenfurther washed with brine and dried over sodium sulfate. The solvent wasevaporated and the residue was dried under high vacuum to yield theintermediate (10.0 g, 93.85%). A 100 mL dry flask was charged withmethyl 2-methoxynicotinate (2.50 g, 15 mmol), 10 mL anhydrous DMF andNaH (0.9 g, 22.5 mmol, 60% in oil). The intermediate (2.58 g, 15.7 mmol)in 3 mL anhydrous DMF was added and the reaction was stirred for 2hours. The mixture was poured into 120 mL of water with 3 mL AcOH. Theyellow solid was further wash with water and passed through a column(hexane:EtOAc 3:1) to give the methoxy intermediate (3.4 g, 75.7%). A 50mL flask was charged with the methoxy intermediate (1.0 g, 3.3 mmol) andpyridine hydrogen chloride (4.0 g, 33 mmol) and heated to 190° C. for 3h. The mixture was poured into a sodium bicarbonate solution and thesolid was collected by filtration, washed with EtOAc and MeOH (20 mLeach) to give2-(4-hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one (0.58 g,69.4%). MS (ES) m/z: 254.0 (M+1); Mp. 300-302° C.

Example 39

2-(4-Hydroxyphenyl)-4H-pyrano[3,2-c]pyridin-4-one

A solution of 4-chloropicolinic acid (3.0 g, 19.04 mmol) in EtOH (100mL) was mixed with H₂SO₄ (conc., 5 mL) and was stirred at reflux for 48h. The reaction mixture was cooled to rt and neutralized with NaOH (1 N)to adjust pH=8-9. The mixture was extract with dichloromethane (3×100mL) and concentration to afforded ethyl 4-ethoxypicolinate (3.44 g,93%).

To a solution of ethyl 4-ethoxypicolinate (3.44 g, 17.43 mmol) and4-methoxy acetophenone (2.62 g, 17.43 mmol) in THF (100 mL) and DMSO (50mL) was added NaH (1.4 g, 34.80 mmol). The resulting mixture was stirredat 95° C. for 6 h. The reaction mixture was cooled to rt and quenchedwith water (100 mL). The mixture was extract with EtOAc (3×150 mL) andconcentration to a yellow solid. The solid was washed with hexanes toafford the diketone (3.6 g, 69%).

The diketone (1 g, 3.34 mmol) was mixed with pyridine hydrochloride (10g). This mixture was stirred at 190° C. under N₂ for 12 h. The mixturewas then diluted with EtOAc (30 mL) and poured into a beaker of 200 mLice water. NaOH (1 N) was used to adjust pH=9. The solid was thenfiltered off and washed with water, hexanes, dichloromethane, EtOAcsequentially to afford the brownish solid2-(4-hydroxyphenyl)-4H-pyrano[3,2-c]pyridin-4-one (0.39 g, 49%). MS (ES)m/z: 240.92 (M+1), 239.89 (M); Mp. 306-308° C.

Example 40

4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile

Methyl 2-methoxynicotinitate was synthesized from Ethyl2-chloronicotinitate with sodium methoxide as described in Example 34. Adry 50 mL flask was charged with methyl 2-methoxynicotinitate (2.50 g,14.9 mmol) and 4-acetylbenzonitrile (2.25 g, 15.9 mmol) and anhydrousDMF (10 mL). NaH (0.745 g, 18.6 mmol, 60% in oil) was added and thereaction mixture was stirred for 30 min. then poured into 100 mL waterand AcOH (2 mL) to adjust pH to 6-7.0. The yellow solid was furtherwashed with water and dissolved in dichloromethane. The organic solutionwas washed with brine and dried over sodium sulfate. The solvent wasremoved and the residue was purified by column chromatography(hexane:EtOAc 3:1) to give the intermediate (1.7 g, 40.7%). A 50 mLflask was charged with the intermediate (0.7 g, 2.49 mmol) and pyridinehydrogen chloride (2.87 g, 24.9 mmol) and heat to 190° C. for 1 h. Themixture was poured into a sodium bicarbonate solution and the solid wascollected and purified by column chromatography(hexane:EtOAc:dichloromethane 1:1:1, then dichloromethane:methanol 1:1)to give 320 mg (51.7%) of4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile. MS (ES) m/z: 249.80(M+1), 248.90 (M); Mp. 250-252° C.

Example 41

2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one

Sodium methoxide (18 mL, 25 wt % in methanol) was added slowly to asolution of ethyl-2-chloronicotinate (11.134 g 60 mmol) in 60 mLanhydrous methanol. The reaction mixture was stirred under reflux for 15h, then cooled to rt. Methanol was removed in vacuo. The residue wasdissolved in EtOAc (200 mL) and saturated aqueous ammonium chloride (50mL) was added. The organic layer was separated and dried over anhydrousNa₂SO₄. The solvent was removed to give ethyl-2-methoxynicotinate (8.58g, 79%). Sodium hydride (60% in mineral oil, 0.48 g, 12 mmol) wasdissolved in anhydrous DMF (10 mL). A solution of 3′-chloro-4′-methoxyacetophenone (1.85 g, 10 mmol) in anhydrous DMF (5 mL) was addeddrop-wise at 0° C. under nitrogen. The mixture was stirred at 0° C. for5 min. and then at rt for 30 min. The mixture was cooled to 0° C. Asolution of ethyl 2-methoxy nicotinate (1.81 g, 10 mmol) in anhydrousDMF (5 mL) was added slowly. The ice bath was removed and the mixturewas stirring at rt under nitrogen for 20 h. Water (20 mL) was added andthe mixture was extracted with EtOAc (2×100 mL). The combined organiclayers were washed with brine and dried over anhydrous Na₂SO₄. Removalof solvent gave a dark colored solid. Triturating with ether gave ayellow solid (1.64 g, 51%). The yellow solid (1.36 g, 4.21 mmol) andpyridinium hydrochloride (7.3 g, 63.2 mmol) were mixed together andstirred at 190° C. for 2 h, then cooled to rt. Water (100 mL) was added.The solid was separated by filtration, washed with water and dried undervacuum. The crude compound was purified by column chromatography (SilicaGel 230-400 mesh; 5% methanol in dichloromethane as an eluent to afford2-(3-chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (0.385 g,33% yield) as yellow solid. MS (ES) m/z: 275.94+273.92 (two isotopes ofM); Mp. 259-262° C.

Example 42

2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one

Sodium methoxide (18 mL, 25 wt % in methanol) was added slowly to asolution of ethyl-2-chloronicotinate (11.14 g 60 mmol) in anhydrousmethanol (60 mL). The reaction mixture was stirred under reflux for 15h, then cooled to rt. The methanol was removed in vacuo. The residue wasdissolved in EtOAc (200 mL) and sat. ammonium chloride solution (50 mL)was added. The organic layer was separated and dried over anhydrousNa₂SO₄. Removal of solvent gave ethyl-2-methoxynicotinate (8.58 g, 79%)as yellow oil. Sodium hydride (0.21 g, 60% in mineral oil, 5.16 mmol)was mixed with anhydrous DMF (5 mL). A solution of3′-bromo-4′-methoxyacetophenone (0.99 g, 4.3 mmol) in anhydrous DMF (3mL) was added drop-wise at 0° C. under nitrogen. The mixture was stirredat 0° C. for 5 min. and then at rt for 30 min. The mixture was cooled to0° C. A solution of ethyl 2-methoxy nicotinate (1.81 g, 10 mmol) inanhydrous DMF (3 mL) was added slowly. The ice bath was removed and thestirring continued at rt under nitrogen for 20 h. Water (20 mL) wasadded and the mixture was extracted with EtOAc (2×100 mL). The organiclayer was washed with brine and dried over anhydrous Na₂SO₄. Removal ofthe solvent gave a dark solid. Triturating with ether gave a yellowsolid (1.32 g, 84%). The solid (1.31 g, 3.6 mmol) and pyridiniumhydrochloride (6.24 g, 54 mmol) were mixed together and stirred at 190°C. for 3 h, The reaction mixture was then cooled to rt, followed by theaddition of water (200 mL). The solid was isolated by filtration, washedwith water and dried under vacuum. The crude compound was purified bycolumn chromatography (Silica Gel 230-400 mesh; 5:4:1 hexanes, EtOAc andmethanol as an eluent) to give2-(3-bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.453 g, 40%)of as yellow solid. MS (ES) m/z: 317.84, 239.9; Mp. 267-272° C.

Example 43

2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one

A solution of ethyl 2-chloronicotinitate (6.0 g, 0.0323 mol) inanhydrous methanol (10 mL) at rt was added sodium methoxide (10 mL, 25%in methanol). The reaction mixture was stirred for half hour then heatedto reflux for one hour. The mixture was poured into water and extractedwith ethyl acetate and the organic layer was washed with water untilneutral, dried over sodium sulfate, and concentrated to give methyl2-methoxynicotinitate (5.2 g, 96.3%).

A 100 mL dry flask was charged with acetovanillone (4.16 g, 0.025 mol)and anhydrous DMF (10 mL). Sodium hydride (1.05 g, 0.0263 mol, 60% inmineral oil) was added and the reaction mixture was stirred at rtfollowed by the dropwise addition of benzyl bromide (3.1 mL, 0.0263mol). The reaction was carried out at rt for 2 h, then poured intowater. Ethyl acetate (150 mL) was used to extract out the compound andthe organic layer was washed with water (2×100 mL), brine, dried oversodium sulfate, and concentrated to give the benzyl intermediate (6.21g, 96%), which was subsequently used without further purification.

A 100 mL dry flask was charged with methyl 2-methoxynicotinitate (2.2 g,0.0131 mol), the benzyl intermediate (3.37 g, 0.0131 mol) and anhydrousDMF (10 mL). Sodium hydride (0.524 g, 0.0131 mol, 60% in mineral oil)was added and the reaction mixture was stirred for 2 hours at rt. Thereaction mixture was poured into water and extracted with ethyl acetate(150 mL). The organic layer was washed with water (2×100 mL), brine (100mL), dried over sodium sulfate, and concentrated to give theintermediate (5.0 g, 97.6%). This intermediate (4.0 g, 0.0102 mol) andpyridine hydrochloride (12.0 g, 0.102 mol) were mixed and heated to170-190° C. for 20 min. The reaction mixture was cooled and poured intowater (100 mL). The mixture was extracted with ethyl acetate (3×200 mL),and the combined organic layers were washed with brine (3×100 mL), driedover sodium sulfate, and concentrated. The solid was further purified byrefluxing with methanol (40 mL). The solution was cooled and filtered toyield 2-(4-hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (250mg, 9.1%). MS (ES) m/z: 270.92, 269.91; Mp. 253-255° C.

Example 44

2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one

In a 500 mL dry round bottom flask with reflux condenser and magneticstirrer was placed with 2-chloro-3-ethyl nicotinate (40.0 g, 215.5 mmol)in methanol (200 mL), and sodium methoxide (65 mL, 301.7 mmol, 25% inmethanol) was added slowly and the reaction mixture was refluxed for 16h. The reaction mixture was cooled to rt and the reaction was quenchedby addition of saturated aqueous NH₄Cl solution, followed by extractionwith ethyl acetate. The combined organic layers were washed well withwater, brine, dried over Na₂SO₄ and concentrated to give2-methoxy-3-methyl nicotinate (35 g, 97%). To a dry 500 mL round bottomflask was added NaH (9.21 g 230.3 mmol, 60% in mineral oil) in DMF (100mL). 4-Methoxyacetophenone (31.45 g, 209.44 mmol) in dry DMF (50 mL) wasadded dropwise at 0° C. over 30 minutes. The reaction mixture wasstirred for 1 h at rt. Then 2-methoxynicotinic acid methyl ester (35 g,209.44 mmol) dissolved in dry DMF (50 mL) was added slowly on cooling.The mixture was stirred for 16 h at rt. The reaction was quenched byaddition of saturated NH₄Cl solution and diluted with water. The solidwas filtered off, washed with water and dried to give the diketo product(56.7 g, 95%). Polyphosphoric acid (8.0 g) was heated at 90° C. and thediketo compound (1.0 g, 3.50 mmol) was added slowly and heated at 90° C.for 1 h. The reaction mixture was cooled to rt and diluted with water.The solid was isolated by filtration, washed with water and dried togive 2-(4-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (570 mg, 64%).MS (ES) m/z: 254.89 (M+1), 253.90 (M); Mp. 269-270° C.

Example 45

2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one

In a 100 mL dry round bottom flask with reflux condenser and magneticstirrer was placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (1.0g, 4.18 mmol) in EtOH (10 mL) and acetonitrile (50 mL). 2-Chloroethanol(2.05 g, 25.0 mmol) was added slowly and the reaction mixture wasrefluxed for 48 h. The reaction mixture was cooled to rt andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography, using 2% MeOH in dichloromethane to afford2-(4-(2-hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one (380 mg,32% yield). MS (ES) m/z: 284.94 (M+1), 283.95 (M); Mp. 157-159° C.

Example 46

2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 5-amino-2-cyano pyridine (1.0 g, 8.38 mmol), conc.H₂SO₄ (4.2 mL), water (15 mL) and the mixture was cooled to 0° C. Asolution of NaNO₂ (636 mg, 9.22 mmol) in water (5.7 mL) was added slowlyat 0° C. Then the reaction mixture was stirred for 30 min at 0° C. Thereaction mixture was poured into a boiling mixture of water (11 mL) andH₂SO₄ (1 mL) and stirred for 30 min. The mixture was cooled andextracted with EtOAc. The organic layer was washed with water, dried andconcentrated to give 2-cyano-5-hydroxy pyridine (900 mg, 89%).

2-Cyano-5-hydroxy pyridine (200 mg, 1.66 mmol), DMF (10 mL) and K₂CO₃(253 mg, 1.83 mmol), and MeI (354 mg, 2.49 mmol) were combined at rt andthe reaction mixture was stirred for 24 h at rt. The reaction mixturewas poured into water and extracted with EtOAc. The organic layer wasseparated, washed with water, dried and concentrated to give2-cyano-5-methoxy pyridine (175 mg, 78%).

2-Cyano-5-methoxy pyridine (170 mg, 1.26 mmol) was dissolved in 6N HCl(4 mL) and refluxed for 16 h. The reaction mixture was cooled to rt anddiluted with water, neutralized and extracted with EtOAc. The organiclayer was washed with water, brine, dried and concentrated to give acrude (290 mg).

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxy acetophenone (3.56 g, 26.14 mmol),5-methoxy-2 nicotinic acid (4.0 g, 26.14 mmol) and pyridine (50 mL).POCl₃ (4 g, 26.14 mmol) was added slowly on cooling. Then the reactionmixture was stirred for 24 h at rt under N₂. The reaction mixture waspoured into ice-water and extracted with EtOAc. The organic layer waswashed with water, dried and concentrated to give 2-acetylphenyl5-methoxypyridine-2-carboxylate (1.76 g, 24%).

To a solution of 2-acetylphenyl 5-methoxypyridine-2-carboxylate (1.76 g,6.49 mmol) in THF (30 mL), was added potassium t-butoxide (952 mg, 7.79mmol) and the reaction mixture was stirred for 24 h at rt under N₂. Thereaction mixture was poured into saturated solution of NH₄Cl. Theorganic layer was separated, washed with water, dried and concentratedto give crude product which was purified by using column chromatographyusing 50% EtOAc in hexane to give1-(2-hydroxy-phenyl)-3-(4-methoxy-pyridin-2-yl)-propane-1,3-dione (870mg, 49%).

1-(2-Hydroxy-phenyl)-3-(4-methoxy-pyridin-2-yl)-propane-1,3-dione (870mg, 3.21 mmol) was dissolved in a mixture of 48% HCl (1 mL) and AcOH (10mL) and heated at 100° C. for 1 h. The reaction mixture was cooled tort, diluted with water and extracted with EtOAc. The organic layer waswashed with water, brine, dried and concentrated to give2-(5-methoxy-pyridin-2-yl)-chromen-4-one (794 mg, 98%).

2-(5-Methoxy-pyridin-2-yl)-chromen-4-one (790 mg, 3.12 mmol) in HI (10mL) and AcOH (4 mL) was heated at reflux for 6 h. Reaction mixture wascooled to rt, diluted with water, neutralized and extracted with EtOActo give crude product. This was purified by column chromatography using5% MeOH in dichloromethane to give (270 mg, 36%) of2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one. MS (ES) m/z: 240.09 (M+1).

Example 47

2-Pyridin-4-yl-chromen-4-one

2-Hydroxyacetophenone (1.36 g, 10 mmol) and isonicotinyl chloridehydrochloride (1.78 g, 10 mmol) were dissolved in 20 mL anhydrouspyridine and stirred at rt for 15 h under nitrogen. Water (20 mL) wasadded and neutralized to pH 6 with 4N HCl. The formed solid was filteredoff, washed with water and dried to give isonicotinic acid-2-acetylphenyl ester as a white powder (2.32 g, 96%). To a solution ofisonicotinic acid-2-acetyl phenyl ester (2.2 g, 9.12 mmol) in 20 mLanhydrous pyridine was added powdered potassium hydroxide (1.54 g, 27.36mmol) and stirred at rt for 15 h under nitrogen. Water (50 mL) was addedand the pH was adjusted to pH 6 with 4N HCl. The solid formed wasfiltered off, washed with water and dried to give a yellow powder (0.66g). The aqueous phase was extracted with EtOAc. The organic layer waswashed with brine, dried over anhydrous Na₂SO₄, and concentrated to givea yellow solid (1.32 g, 60%). The compound (0.64 g, 2.654 mmol) wassuspended in 6 mL glacial AcOH. Three drops of conc. HCl was added andthe mixture was stirred at 110° C. for 3 h. The mixture was cooled tort. Water (20 mL) was added and the mixture was neutralized to pH 6-7with a 2 N NaOH solution. The white precipitate formed was filtered off,washed with water and dried under vacuum to give2-pyridin-4-yl-chromen-4-one (0.56 g, 94.5%). MS (ES) m/z: 224.89 (M+1),223.92 (M); Mp. 144-145° C.

Example 48

2-(6-Hydroxypyridin-3-yl)-chromen-4-one

In a 100 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2′-hydroxy acetophenone (2.0 g, 14.69 mmol),2-methoxy-5-pyridine carboxylic acid (2.0 g, 14.69 mmol) and pyridine(20 mL). POCl₃ (2.25 g, 14.69 mmol) was added slowly on cooling. Thereaction mixture was stirred for 24 h at rt under nitrogen. The reactionmixture was poured into ice-water and extracted with EtOAc. The organiclayer was washed with water, dried and concentrated to give product(2.82 g, 70%). To a solution of this product (2.8 g, 10.33 mmol) in THF(50 mL) was added potassium t-butoxide (1.51 g, 12.4 mmol) and thereaction mixture was stirred for 3 h at rt under N₂. The reactionmixture was poured into a saturated aqueous solution of NH₄Cl. Theorganic layer was separated, washed with water, dried and concentratedto give crude diketone (2.8 g, 99%). The diketone (2.8 g, 10.33 mmol)was dissolved in a mixture of 36% HCl (2 mL) and AcOH (25 mL) and heatedat 100° C. for 1 h. The reaction mixture was cooled to rt, diluted withwater and extracted with EtOAc. The organic layer was washed with water,brine, dried and concentrated to give the crude cyclized product (1.96g, 74%). A mixture of the cyclized product (500 mg, 1.97 mmol) andpyridinium hydrochloride (5 g) was heated at 190° C. for 1 h. Thereaction mixture was cooled to rt, diluted with water, neutralized withNaHCO₃ and filtered to give 2-(6-hydroxypyridin-3-yl)-chromen-4-one (480mg, 98%). MS (ES) m/z: 240.92 (M+1), 239.89 (M); Mp. 296-297° C.

Example 49

5,7-Dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer, 3,5-dimethoxy aniline (1.0 g, 6.52 mmol) and polyphosphoricacid (12 g) were taken. The mixture was heated 90-100° C. Then 4-hydroxybenzoyl methyl ester (1.26 g, 6.52 mmol) was added slowly over 1.5 h.After addition reaction mixture was heated for further 2 h. The reactionmixture was cooled to rt, and diluted with water. The precipitates werefiltered to give a crude product, which was heated at 100° C. inconcentrated HCl (10 mL) for 3 h. Then cooled the reaction mixture to rtand filtered the precipitates. The product was purified by columnchromatography using 10% MeOH in dichloromethane to give 50 mg of5,7-dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one. MS (ES) m/z: 298.21(M+1), and 284.20.

Example 50

5,7-Dihydroxy-2-(4-hydroxyphenyl)-quinolin-4(H)-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer, 5,7-dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one (1.0 g, 3.36mmol) and 48% HBr (15 mL) were taken. The mixture was heated to refluxfor 5 h. The reaction mixture was cooled to rt, and the water wasremoved under reduced pressure to give a crude product, which waspurified by column chromatography using DCM:EtOAc:MeOH (6:3:1) to give100 mg of 5,7-dihydroxy-2-(4-hydroxyphenyl)-quinolin-4(H)-one (11%). MS(ES) m/z: 270.13 (M+1).

Example 51

2-(4-Hydroxy-phenyl)-1H-quinolin-4-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-amino acetophenone (1.0 g, 7.39 mmol), THF (15 mL)and Et₃N (2.39 g, 23.64 mmol). To the solution p-methoxy benzoylchloride (1.32 g, 7.76 mmol) in THF (15 mL) was added slowly at 0° C.and stirred for 30 min at 0° C. Then the reaction mixture was stirredfor 24 h at rt under nitrogen. The reaction mixture was poured into icewater. The crude product was collected and crude product was purified bycolumn chromatography using 25% EtOAc in hexane to give 1.865 g ofN-(2-acetylphenyl)-4-methoxybenzamide (93%).

To a suspension of N-(2-acetylphenyl)-4-methoxybenzamide (0.865 g, 3.2mmol) in t-butanol (12 mL), was added potassium t-butoxide (1.57 g, 12.8mmol). The reaction mixture was heated at 70° C. for 24 h under N₂, Themixture was cooled to rt and poured into 30 mL of saturated NH₄Cl. Thesolids were collected and purified by column chromatography using 10%MeOH in DCM to give 398 mg of1-(2-amino-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (49%).

1-(2-Amino-phenyl)-3-(4-methoxy-phenyl)-propane-1,3-dione (375 mg, 1.49mmol) was dissolved in 48% HBr (15 mL) and refluxed for 16 h. Thesolvent was removed at reduced pressure. The solids were taken intowater and neutralized by NaHCO₃. Solids were collected and purified bycolumn chromatography using 5% MeOH in DCM to give 350 mg of2-(4-hydroxy-phenyl)-1H-quinolin-4-one (98%). MS (ES): m/z: 238.1 (M+1).

Example 52

2-(4-Ethoxycarbonyloxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acidethyl ester

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(4-hydroxy-phenyl)-1H-quinolin-4-one (250 mg,1.054 mmol), DCM (30 mL), ethylchloroformate (252 mg, 2.32 mmol) andEt₃N (234 mg, 2.32 mmol) and stirred for overnight at rt. Solvent wasremoved and crude product was purified by column chromatography usingDCM to gave 240 mg of2-(4-ethoxycarbonyloxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acidethyl ester (50%). MS (ES) m/z: 382.23 (M+1), 324.21, and 310.18.

Example 53

3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one

To a solution of n-methyl-o-toluamide (2.0 g, 13.4 mmol) in THF (30 mL),n-butyl lithium (12.3 mL, 30.8 mmol, 2.5 M solution in hexane) was addedslowly under N₂ with cooling (ice-salt bath) maintaining the temperaturebelow 20° C. After addition, the mixture was stirred for 1 h at 0° C.,then cooled to −50° C. A solution of 4-methoxy benzonitrile (2.14 g,16.08 mmol) in THF (5 mL) was added quickly. The cooling bath wasremoved and the reaction was allowed to warm to rt. A saturated aqueousNH₄Cl solution was added during cooling, and the solid was isolated byfiltration to give the methoxy compound (2.2 g, 65%). The methoxycompound (750 mg, 2.98 mmol) was dissolved in a 50 mL flask andpyridinium hydrochloride (10 g) was added. The mixture was heated at190° C. for 2 h, then cooled to rt. The reaction was then diluted withwater, neutralized with NaHCO₃ and the solid was isolated by filtrationto give 600 mg of 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (84%). MS(ES) m/z: 238.92 (M+1), 237.89 (M); Mp. 239-241° C.

Example 54

4-Isoquinolin-3-yl-phenol

To a solution of 2-bromobenzaldehyde (1.85 g, 10 mmol) and4-methoxyphenyl acetylene (1.58 g, 12 mmol) in 40 mL of triethylaminewere added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol%) and copper(I) iodide (20 mg, 1 mol %). The reaction mixture washeated at 50° C. under nitrogen for 3 h. The reaction mixture was cooledto room temperature and the ammonium salt was removed by filtration. Thefiltrate was concentrated under reduced pressure. Purification of thecrude compound by column chromatography (SilicaGel 230-400 mesh; 10%ethyl acetate in hexanes as eluent) afforded of 2-(4-methoxyphenylethynyl)benzaldehyde (2.1 g, 89%).

2-(4-Methoxy phenylethynyl)benzaldehyde (2.06 g, 8.73 mmol) andt-butylamine (3.83 g, 52.4 mmol) were stirred under nitrogen for 24 h atroom temperature. The resulting mixture was extracted with ether and theorganic layer was dried over anhydrous Na₂SO₄, concentrated to give theimine (2.4 g, 94%) which was used in the next step without furtherpurification. To a solution of this imine (2.39 g, 8.2 mmol) in 100 mLanhydrous DMF was added (0.156 g, 0.82 mmol) copper(I) iodide andflushed with nitrogen. The reaction mixture was heated at 100° C. for 4h. The mixture was cooled to room temperature, and diluted with ether(200 mL). The organic layer was washed with saturated aqueous ammoniumchloride (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated to give the crude compound as a dark coloured solid.Purification by column chromatography (SilicaGel 230-400 mesh; 10%ethylacetate in hexanes as eluent) afforded3-(4-methoxyphenyl)isoquinoline (1.064 g, 55%) as a white solid. The3-(4-methoxyphenyl)isoquinoline (1.05 g, 4.47 mmol) was suspended in 30mL hydroiodic acid and 12 mL of acetic acid was added. The reactionmixture was stirred at 110° C. for 2 h, then cooled to room temperature.The precipitate formed was filtered off, washed with acetic acid (2×5mL) and dried under vacuum to give a yellow solid. The crude compoundwas purified by triturating with 5% methanol in ether to give4-isoquinolin-3-yl-phenol (0.83 g, 84%) as a white powder. MS (ES) m/z:222.89 (M+1), 221.86 (M); Mp. 218-219° C.

Example 55

4-(Isoquinolin-3-yl)phenol hydrochloride

HCl (0.4 mL, 2 N) was added to 4-isoquinolin-3-yl-phenol (0.044 g, 0.2mmol) and the solution was heated at 60° C. for 10 min, resulting in ayellow solid. The reaction mixture was evaporated to dryness to give4-(isoquinolin-3-yl)phenol hydrochloride (0.45 g, 77%). MS (ES) m/z:222.96 (M+1), 221.95 (M); ¹³C-NMR (DMSO-d₆): δ 180.2, 149.9, 138.8,130.0, 129.6, 129.5, 127.8, 126.7, 116.7.

Example 56

7-(3-Fluoro-4-hydroxyphenyl)-6-methyl-1,6-naphthyridin-5(6H)-one

A suspension of 2-methyl nicotinic acid (1.5 g, 10.94 mmol) in DCM (30mL), triethylamine (1.16 g, 11.48 mmol) and oxlyl chloride (2.77 g,21.87 mmol) were stirred at rt for 16 h. The solvent and excess ofoxalyl chloride were removed at reduced pressure. The solid wasdissolved in DCM (10 mL) and methylamine hydrochloride (1.02 g, 32.81mmol) was added on cooling followed by stirring at rt for 4 h. Thesolvent was removed and the crude product was purified by chromatographyby using 5% MeOH in DCM to give 1.4 g of the amide product (95%). To asolution of the amide (1.35 g, 8.99 mmol) in THF (25 mL), was slowlyadded n-butyl lithium (8.3 mL, 20.68 mmol, 2.5 M solution in hexane)under N₂ with cooling (ice-salt bath), maintaining the temperature below20° C. After addition, the mixture was stirred for 1 h at 0° C. Themixture was cooled to −50° C. and a solution of 4-methoxy-3-fluorobenzonitrile (1.63 g, 10.79 mmol) in THF (10 mL) was added quickly. Thecooling bath was removed and the mixture was allowed to warm to rt.Saturated NH₄Cl solution was added under cooling, and the layers wereseparated. The organic layer was washed with water, brine, and driedover Na₂SO₄. After concentration, the crude product was purified bychromatography using 5% MeOH in DCM to give 918 mg of the enamine (34%).To a suspension of the enamine (400 mg, 1.33 mmol) in EtOH (15 mL) wasadded conc. HCl (2 mL). The mixture was heated at 80° C. for 2 h. Thereaction mixture was cooled to rt and the solvent was removed to give400 mg of crude methoxy compound (94%). In a 50 mL flask were placed themethoxy compound (400 mg, 1.40 mmol) and pyridinium hydrochloride (6 g),followed by heating of the mixture at 190° C. for 4 h. The flask wasthen cooled to rt, diluted with water, neutralized with NaHCO₃ and thesolid was filtered to afford 160 mg of7-(3-fluoro-4-hydroxyphenyl)-6-methyl-1,6-naphthyridin-5(6H)-one (42%).MS (ES) m/z: 271.97 (M+1), 270.96 (M); Mp. 182-184° C.

Example 57

4-(1,6-Naphthyridin-7-yl)phenol

To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL)were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol%) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture washeated at 50° C. under nitrogen for 3 h, then cooled to roomtemperature. The ammonium salt was removed by filtration. The filtratewas concentrated under reduced pressure leaving 2-(4-methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as yellow solid.2-(4-Methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol)and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24h at rt. The resulting mixture was extracted with ether and dried overanhydrous Na₂SO₄. Removal of solvent gave the imine (2.72 g, 97%) whichwas used in next step without further purification. To a solution ofthis imine (2.7 g, 9.23 mmol) in 50 mL anhydrous DMF was added (0.190 g,0.1 mmol) copper (I) iodide. The reaction mixture was heated at 100° C.for 4 h, then cooled to room temperature and diluted with ether (200mL). The organic layer was washed with sat. aqueous ammonium chloridesolution (3×100 mL). The organic layer was dried over anhydrous Na₂SO₄.Removal of solvent gave the crude compound as a dark colored solid.Purification by column chromatography (Silica Gel 230-400 mesh; 30%ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl)[1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of7-(4-methoxy phenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrousN-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol)and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture wasstirred at 190° C. for 1 h under nitrogen. The reaction mixture wascooled to room temperature. The crude compound was adsorbed onto silicagel and purified by column chromatography (Silica Gel 230-400 mesh;20-70% ethyl acetate in hexanes as fluent) to give4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. MS(ES) m/z: 223.95 (M+1), 222.95 (M); Mp. 219-221° C.

Example 58

2-Fluoro-4-(5-methoxy-1-(methylamino)isoquinolin-3-yl)phenol

To a suspension of 2-methyl-3-methoxy benzoic acid (2.0 g, 12.03 mmol)in CH₂Cl₂ (30 mL), oxalyl chloride (3.05 g, 24.07 mmol) was added andstirred at room temperature for 16 h. The solvent and excess of oxalylchloride were removed at reduced pressure. The solid was dissolved inCH₂Cl₂ (10 mL) and methyl amine (1.12 g, 36.1 mmol) was added on coolingand the mixture was stirred at room temperature for 4 h. The solvent wasremoved and the crude product was purified by chromatography using 5%methanol in CH₂Cl₂ to give the amide product (1.67 g, 78%). To asolution of the amide (946 mg, 5.28 mmol) in THF (20 mL) was addedn-butyl lithium (4.85 mL, 12.14 mmol, 2.5 M solution in hexane) wasadded slowly under N₂ with cooling (ice-salt bath) maintainingtemperature below −20° C. After completion of addition, the mixture wasstirred for 1 h at 0° C., then cooled to −50° C. and a solution of4-O-TBDMS-3-fluoro benzonitrile (1.46 g, 5.8 mmol) in THF (10 mL) wasadded quickly. The cooling bath was removed and the reaction mixture wasallowed to warm to room temperature. Saturated NH₄Cl solution was addedunder cooling. The organic layer was washed with water, brine, driedover Na₂SO₄ and concentrated to give the crude product, which waspurified by chromatography using 5% methanol in CH₂Cl₂, to give twoproducts: An enamine (260 mg) and a cyclized product (450 mg). To asuspension of the enamine (400 mg, 1.33 mmol) in ethanol (15 mL), conc.HCl (2 mL) was added and heated at 80° C. for 2 h. The reaction mixturewas cooled to room temperature and the solvent was removed andneutralized by NaHCO₃ to give2-fluoro-4-(5-methoxy-1-(methylamino)isoquinolin-3-yl)phenol (150 mg,83%). MS (ES) m/z: 300.01 (M+1), 299.00 (M); Mp. 185-187° C.

Example 59

3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1(2H)-one

To a suspension of 2-methyl-3-methoxy benzoic acid (2.0 g, 12.03 mmol)in DCM (30 mL), oxalyl chloride (3.05 g, 24.07 mmol) was added andstirred at rt for 16 h. The solvent and excess of oxylyl chloride wereremoved at reduced pressure. The solid was dissolved in DCM (10 mL) andmethyl amine (1.12 g, 36.1 mmol) was added on cooling and the mixturewas stirred at rt for 4 h. The solvent was removed and the crude productwas purified by chromatography using 5% MeOH in DCM to give the amideproduct (1.67 g, 78%). To a solution of the amide (946 mg, 5.28 mmol) inTHF (20 mL) was added n-butyl lithium (4.85 mL, 12.14 mmol, 2.5 Msolution in hexane) was added slowly under N₂ with cooling (ice-saltbath) maintaining temperature below −20° C. After completion ofaddition, the mixture was stirred for 1 h at 0° C., then cooled to −50°C. and a solution of 4-O-TBDMS-3-fluoro benzonitrile (1.46 g, 5.8 mmol)in THF (10 mL) was added quickly. The cooling bath was removed and thereaction mixture was allowed to warm to rt. Saturated NH₄Cl solution wasadded under cooling. The organic layer was washed with water, brine,dried over Na₂SO₄ and concentrated to give the crude product, which waspurified by chromatography using 5% MeOH in DCM, to give two products:an enamine (260 mg) and a cyclized product (450 mg). To a suspension ofthe cyclized product (450 mg, 1.1 mmol) in EtOH (15 mL), conc. HCl (2mL) was added and heated at 60° C. for 3 h. The reaction mixture wascooled to rt and the solvent was removed and purified by chromatographyusing 5% MeOH in DCM to give 85 mg of product (26%). MS (ES) m/z:286.11; Mp. 289-291° C.

Example 60

3-(4-Hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.27mmol) in CH₂Cl₂ (30 mL), oxalyl chloride (3.62 g, 28.54 mmol) was addedand the mixture was stirred at rt for 16 h. The solvent and excess ofoxalyl chloride were removed at reduced pressure. The solid wasdissolved in CH₂Cl₂ (10 mL) and methyl amine hydrochloride (1.33 g,42.81 mmol) was added on cooling and the mixture was stirred at rt for 4h. The solvent was removed and the crude product was purified bychromatography by using 5% methanol in CH₂Cl₂, to give 1.3 g of theamide intermediate in 43% yield. To a solution of the amide intermediate(1.29 g, 6.16 mmol) in THF (30 mL), n-butyl lithium (5.6 mL, 14.18 mmol,2.5 M solution in hexane) was added slowly under N₂ with cooling(ice-salt bath) maintaining the temperature below 20° C. The mixture wasstirred for 1 h at 0° C., then cooled to −50° C. and a solution of4-O-TBDMS-benzonitrile (1.58 g, 6.78 mmol) in THF (10 mL) was addedquickly. The cooling bath was removed and allowed to warm to rt andstirred for 16 h at rt. Saturated aqueous NH₄Cl solution was added withcooling, and the layers were separated. The organic layer was washedwith water, brine, dried over Na₂SO₄ and concentrated to give the crudeintermediate, which was purified by chromatography using 5% methanol inCH₂Cl₂, to give two products (1) 678 mg of isoquinoline in 26% yield and(2) 780 mg of quinalone product in 27% yield. To a suspension of theabove quinalone product (2) (780 mg, 1.65 mmol) in ethanol (20 mL),conc. HCl (2 ml) was added and the mixture was heated at 70° C. for 2 h.The reaction mixture was cooled to rt and the solvent was removed andpurified by chromatography using 5% methanol in CH₂Cl₂ to give3-(4-hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)-one (215 mg, 44%). MS(ES) m/z: 297.93 (M); Mp. 245-247° C.

Example 61

3-(4-Hydroxyphenyl)naphthalene-1-ol

A 100 mL flask equipped with a condenser was charged with phenylacetylchloride (5.8 mL 0.0435 mol) and 4-methoxyphenylacetylene (3.2 g, 0.024mol). The condenser was connected to a drying tube. The flask was heatedfor 16 h at 180° C. under nitrogen using an oil bath. The cooled darkbrown mixture was poured into 30 mL water and DCM was added. The pH wasadjusted to 7.0 by a NaOH solution. The DCM was evaporated and theresidue was passed through a column (hexane:EtOAc:DCM 14:1:1) to give3.4 g (38.2%) of product. A 50 mL flask was charged with the product(0.91 g), 0.138 g KOH, water (0.3 mL) and MeOH (10 mL). The mixture wasstirred for 12 h at rt, followed by neutralization with HCl to pH 7.0.The aqueous phase was extracted with EtOAc and purified via columnchromatography (hexane:EtOAc 10:1) to yield 0.42 g of product (68%). Theproduct 3-(4-methoxy)phenyl-1-naphthol (0.290 g) and 57% HI (8 mL) wereadded to a 50 mL flask with reflux condenser. The flask was heated to110° C. for 7 h, then cool to rt. The pH was adjusted to 7.0 with NaHCO₃solution and extracted with EtOAc. The organic layer was further washedwith brine and dried with sodium sulfate. The residue was washed withDCM to give 234 mg of 3-(4-hydroxyphenyl)naphthalene-1-ol (73.6%). MS(ES) m/z: 236.09 (M), 235.05 (M−1).

Example 62

4-(4H-Chromen-2-yl)-phenol

A suspension of aluminum chloride (680 mg, 5.1 mmol) in dry THF (50 mL)was cooled to 0° C. under nitrogen. LAH (580 mg, 15.5 mmol) was added tothe above solution and the resulting mixture was stirred for 20 min at0° C., and then at rt for additional 20 min, and cooled down to −50° C.4′-Hydroxyflavone (400 mg, 1.7 mmol) dissolved in 60 mL of THF was addedslowly. The reaction mixture was stirred at −50° C. for 2 h and then for2 h at rt. The reaction was quenched by careful addition of water(traces, to decompose LiAlH₄) and the solvent was removed under reducedpressure. The crude product was initially purified by crystallizationfrom MeOH, and then further purified by column chromatography (silicagel, 5-20% EtOAc/hexane) and repeated crystallization from MeOH toafford 109 mg of 4-(4H-chromen-2-yl)-phenol (29%). MS (ES) m/z: 225.10(M+1), 149.04.

Example 63

2-(4-Hydroxy-phenyl)-thiochromen-4-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer, thiophenol (4.0 g, 36.30 mmol) and polyphosphoric acid (6 g)were heated at 90-100° C. Then 4-methoxybenzoyl AcOH methyl ester (4.03g, 18.15 mmol) was added slowly during 1.5 h. After addition, reactionmixture was heated for an additional 2 h. The reaction mixture was thencooled to the rt, diluted with water and precipitates were filtered togive the crude product, which was purified by column chromatographyusing 30% EtOAc in hexane to afford2-(4-methoxyphenyl)-thiochromen-4-one (2.05 g, 43%).

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer, 2-(4-methoxyphenyl)-thiochromen-4-one (500 mg, 1.86 mmol) andDCM (20 mL) were taken. The mixture was cooled to 0° C. and BBr₃ (933mg, 3.72 mmol, 1M solution in DCM) was added slowly at 0° C. Then thereaction mixture was stirred for overnight at rt under N₂. The unreactedBBr₃ was carefully quenched by addition of MeOH under cooling. Solventwas removed under reduced pressure to give crude product, which waspurified by column chromatography using 5% MeOH in DCM to afford2-(4-hydroxy-phenyl)-thiochromen-4-one (380 mg, 80%). MS (ES) m/z:255.02 (M+1).

Example 64

2-(4-Hydroxy-phenyl)-[1,4]naphthoquinone

To a mixture of 2-bromo-1,4-naphthoquinone (1.0 g, 4.22 mmol),4-hydroxyphenylboronic acid (640 mg, 4.64 mmol), potassium phosphate(3.135 g, 14.76 mmol), tricyclohexylphosphine (118 mg, 0.422 mmol),toluene (20 mL) and water (1 mL) was added palladium acetate (47 mg,0.21 mmol) under N₂. The reaction mixture was heated to 100° C. for 3 h.The reaction was cooled to rt and water was added. The mixture wasextracted with EtOAc, and the combined organic extracts were washed withwater and brine. The organic phase was separated, dried and concentratedto give crude product. Purification by column chromatography, using 10%EtOAc in hexane, gave 480 mg of 2-(4-hydroxy-phenyl)-[1,4]naphthoquinone(45%). MS (ES) m/z: 251.03 (M+1).

Example 65

4-Naphthalen-2-yl-phenol

To a mixture of 2-bromonaphthalene (4.0 g, 19.32 mmol),4-hydroxyphenylboronic acid (2.9 g, 21.24 mmol), potassium phosphate(14.35 g, 67.61 mmol), tricyclohexyl phosphine (542 mg, 1.93 mmol),toluene (80 mL) and water (4 mL) was added palladium acetate (217 mg,0.965 mmol) under N₂. The reaction mixture was heated to 100° C. for 24h and then cooled to rt. Water was added and the mixture was extractedwith EtOAc. The organic layer was separated, washed with water, brine,dried and concentrated to give crude product. Purification by columnchromatography using 10% EtOAc in hexane afforded 105 mg of4-naphthalen-2-yl-phenol. MS (ES) m/z: 220.07 (M) and 219.04 (M−1).

Example 66

2-(4-Hydroxy-phenyl)-1,1-dioxo-1H-1λ6-thiochromen-4-one

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(4-hydroxy-phenyl)-thiochromen-4-one (1.298 g, 5.1mmol), Ac₂O (625 mg, 6.12 mmol), Et₃N (619 mg, 6.12 mmol) and catalyticamount of DMAP in DCM (10 mL) and the reaction mixture was stirred for24 h at rt. The reaction mixture was poured into water and extractedwith EtOAc. The organic layer washed with water, dried and concentratedto afford the 2-(4-acetoxy-phenyl)-thiochromen-4-one (1.4 g, 96%).

To a stirred solution of 2-(4-acetoxy-phenyl)-thiochromen-4-one (800 mg,2.69 mmol) in DCM (260 mL), m-CPBA (665 mg, 2.69 mmol) was added and thereaction mixture was stirred at rt for 48 h. The reaction mixture wasdiluted with DCM and washed with NaHCO₃ solution. The organic layer wasseparated, washed with water, brine, dried and concentrated to givecrude product, which was purified by column chromatography, usingEtOAc:hexane:DCM (1:2:7) to give 260 mg of2-(4-acetoxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one.

To a solution of 2-(4-acetoxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one(260 mg, 0.79 mmol) in MeOH:THF (5 mL:5 mL), K₂CO₃ (133 mg, 0.95 mmol)was added and stirred for 2 h at rt Then the reaction mixture wasneutralized by dilute HCl and extracted by EtOAc, the combined organiclayer was washed with water, brine, dried and concentrated to give acrude product, which was purified by column chromatography using 50%EtOAc in hexane, to give 134 mg (59%) of2-(4-hydroxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one. MS (ES) m/z:286.05 (M), 285.01 (M−1); Mp. 222-224° C.

Example 67

2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one

Salicylamide (6.85 g, 50 mmol) and 4-acetoxybenzoyl chloride (10.9 g, 55mmol) were dissolved in 35 mL anhydrous xylene. Anhydrous pyridine (0.5mL) was added and the reaction mixture was refluxed under nitrogen for12 h. Water was removed by a Dean-Stark apparatus. The mixture wascooled to rt, and the xylene was removed under vacuum. Acetone (100 mL)was added and the mixture was stirred for 10 min. The solid was filteredoff, washed with acetone and dried under vacuum to give the crudecompound (3.0 g). The crude compound (1.5 g) was purified by columnchromatography (SilicaGel 70-230 mesh; 2-5% MeOH in DCM as eluent) togive 770 mg of 2-(4-hydroxyphenyl)benzo[e][1,3]oxazin-4-one (12%) aspale yellow solid. MS (ES) m/z: 240.02; Mp. 273-275° C.

Example 68

6-Naphthalen-2-yl-pyridin-3-ol

To a solution of 2-bromo-5-hydroxypyridine (1.04 g, 6 mmol) in 25 mLanhydrous THF was added 2-naphthylboronic acid (1.03 g, 6 mmol) and 2 Maq. sodium carbonate (9 mL, 18 mmol). To this reaction mixture was addedpalladium tetrakistriphenylphosphine (0.7 g, 0.6 mmol) and the mixturewas stirred at rt for 15 h under nitrogen. The reaction mixture wasdiluted with EtOAc, the organic layer was washed with water (50 mL),brine (50 mL) and dried over anhydrous Na₂SO₄. Removal of solvent gave awhite powder which was purified by column chromatography (Silica Gel230-400 mesh; 3% MeOH in DCM) to give 6-naphthalen-2-yl-pyridin-3-ol(0.225 g, 17%). MS (ES) m/z: 222.96 (M+1), 221.93 (M); Mp. 168-169° C.

Example 69

4-(4,4-Dimethyl-4H-chromen-2-yl)phenyl acetate

To a suspension of 4′-hydroxy flavone (500 mg, 2.098 mmol) in toluene(15 mL) was cooled to 0° C. under N₂. The apparatus was evacuated andfilled with N₂ three times and trimethylaluminum solution (2M intoluene, 5.02 mL, 10.05 mmol) was added over 30 min. The resultingmixture was allowed to warm to rt over 3 h and stirred for 14 h at rt.The reaction mixture was quenched by addition of 2 N HCl with cooling,and extracted with EtOAc. The combined organic layers were washed withwater, brine, dried over Na₂SO₄ and concentrated to give crude product,which was purified by chromatography using neutral Al₂O₃, to give thedimethyl product (150 mg, 28%). In a 50 mL round-bottomed flask fittedwith condenser and magnetic stirrer were placed dimethyl product (150mg, 0.59 mmol), Ac₂O (67 mg, 0.65 mmol), DCM (10 mL) and Et₃N (66 mg,0.65 mmol) then the reaction mixture was stirred for 24 h at rt. Thereaction mixture was poured into water and extracted with EtOAc. Theorganic layer was washed with water, dried and concentrated to give 150mg of 4-(4,4-dimethyl-4H-chromen-2-yl)phenyl acetate (85%). MS (ES) m/z:295.95 (M+1), 294.92 (M); Mp. 84-86° C.

Example 70

4-(Benzo[b][1,4]dioxin-2-yl)phenol

A mixture of 4-(benzo[b][1,4]dioxin-2-yl)phenyl acetate (270 mg, 1.0mmol) in MeOH:THF (5 mL:3 mL) and K₂CO₃ (167 mg, 1.2 mmol) was stirredfor 30 min at rt. The solvent was removed under reduced pressure andwater was added. The solution was neutralized by dilute HCl and thesolid was isolated by filtration, washed well with water and dried togive 175 mg of 4-(benzo[b][1,4]dioxin-2-yl)phenol (77%). MS (ES) m/z:225.97 (M), 224.93 (M−1); Mp. 137-140° C.

Example 71

4-(4-oxo-4H-chromen-2-yl)-phenyl nicotinate

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(4-hydroxyphenyl)chromen-4-one (100 mg, 0.419mmol), pyridine (5 mL) and nicotinoyl chloride (223 mg, 1.25 mmol). Thereaction mixture was stirred for 24 h at rt under nitrogen. The solventwas removed under reduced pressure and crude product was purified bycolumn chromatography using 50% EtOAc in hexane to give 100 mg of4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate (69%). MS (ES) m/z: 344.09(M+1).

Example 72

4-(4-oxo-4H-chromen-2-yl)phenyl acetate

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(4-hydroxyphenyl)chromen-4-one (150 mg, 0.63mmol), Ac₂O (96 mg, 0.94 mmol), Et₃N (96 mg, 0.94 mmol) and catalyticamount of DMAP in DCM (2 mL) and then the reaction mixture was stirredfor 24 h at rt. The reaction mixture was poured into water and extractedwith EtOAc. The organic layer washed with water, dried and concentratedto gave 160 mg of acetic acid 4-(4-oxo-4H-chromen-2-yl)phenyl acetate(91%). MS (ES) m/z: 281.15 (M+1), and 239.12.

Example 73

2-(4-(Nicotinoyloxy)phenyl)-4-oxochroman-5,7-diyl dinicotinate

In a 500 mL round-bottomed flask fitted with magnetic stirrer wereplaced naringenin (4′,5,7-trihydroxyflavanone (5 g, 18.37 mmol)), DMF(80 mL) and nicotinic acid (9 g, 73.46 mmol). EDCl (14 g, 73.46 mmol)and DMAP (1 g) were added. The reaction mixture was stirred for 24 h atrt under nitrogen. The solid was filtered and washed with DMF.Crystallization from DCM-MeOH gave 5.2 g of the product. The filtratewas evaporated under reduced pressure and the residue was dissolved inDCM, which was washed with water and evaporated. The crude product waspurified by column chromatography using toluene-acetone (2:1) to give3.0 g of 2-(4-(nicotinoyloxy)phenyl)-4-oxochroman-5,7-diyl dinicotinate(76%). MS (ES) m/z: 588.25 (M+1), 294.75, and 196.83.

Example 74

2-(4-Nicotinoyloxy)phenyl)-oxo-4H-chromene-5,7-diyl dinicotinate

In a 500 mL round-bottomed flask fitted with magnetic stirrer wereplaced apigenin (4′,5,7-trihydroxyflavone (5 g, 18.50 mmol)) andpyridine (250 mL). The mixture was cooled at −10° C. and nicotinoylchloride HCl (16.5 g, 92.70 mmol) was added. Then the reaction mixturewas stirred for 24 h at rt under nitrogen. The solvent was removed underreduced pressure and the residue was dissolved in chloroform, which waswashed with water and evaporated. The crude product was purified bycrystallization from DCM-MeOH to give 7.5 g of2-(4-nicotinoyloxy)phenyl)-oxo-4H-chromene-5,7-diyl dinicotinate (69%).MS (ES) m/z: 586.17 (M+1), 481.11, 293.70.

Example 75

4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate

In a 50 mL round-bottomed flask fitted with condenser and magneticstirrer were placed 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (212mg, 0.89 mmol), Ac₂O (99 mg, 0.97 mmol), and pyridine (5 mL). Thereaction mixture was stirred for 24 h at room temperature. The reactionmixture was poured into water and extracted with EtOAc. The organiclayer washed with water, dried and concentrated to afford4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate (240 mg, 96%). MS(ES) m/z: 282.89 (M+1), 281.92 (M); Mp. 167-169° C.

Example 76

2-Amino-5-guanidino-pentanoic acid 4-(4-oxo-4H-chromen-2-yl)phenyl estertrihydrochloride

To a solution of 4′-hydroxy flavone (277 mg, 1.16 mmol) in DMF (6 mL)were added diisopropyl ethylamine (451 mg, 4.49 mmol), EDCl (245 mg,1.28 mmol), Boc-Argenine (580 mg, 1.22 mmol) and HOBt (157 mg, 1.16mmol) and the mixture was stirred at rt for 24 h under N₂. The reactionmixture was diluted with water and the solid was filtered off. The solidproduct was dissolved in diethyl ether and the organic layer was washedwith water, brine, dried over Na₂SO₄ and concentrated to give theBoc-protected product (730 mg, 90%). To a solution of the Boc-protectedproduct (200 mg, 0.287 mmol) in DCM (15 mL), HCl gas was bubbled throughfor 6 h at 0° C. The solid was filtered off and washed with DCM to give133 mg of 2-amino-5-guanidino-pentanoic acid4-(4-oxo-4H-chromen-2-yl)phenyl ester trihydrochloride (69%). MS (ES)m/z: 394.93 (M-Arg), 238.86.

Example 77

4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate

To a solution of 1,4-benzodioxane (5 g, 36.72 mmol) in CCl₄ (200 mL),NBS (14.38 g, 80.79 mmol) and AIBN (500 mg) were added under N₂. Themixture was heated at reflux for 12 h. The reaction mixture was cooledto rt. The solution was evaporated to give the crude product, which waspurified by chromatography on neutral Al₂O₃ using 10% EtOAc in hexane togive the di-bromo compound (9.34 g, 86%). To a stirred solution of2,3-dibromo-2,3-dihydro-1,4-benzodioxine (9.84 g, 33.45 mmol) in Et₂O(150 mL), was added potassium t-butoxide (4.5 g, 40.14 mmol) under N₂.The mixture was stirred for 3 h at rt. The solid was filtered off andthe solution was concentrated to give the crude product, which purifiedby chromatography on neutral Al₂O₃ using 10% EtOAc in hexane to give2-bromodioxane (6.8 g, 95%). To a mixture of 2-bromodioxane (1.0 g, 4.69mmol), 4-(4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl)phenyl acetate (1.23g, 4.69 mmol), sodium bicarbonate (1.18 g, 14.07 mmol), THF (50 mL) andwater (7 mL) was added tetrakis-triphenyl phosphine palladium (271 mg,0.23 mmol) under N₂. The reaction mixture was heated to 110° C. for 5 hand then cooled to rt. Water was added and the mixture was extractedwith EtOAc. The organic layer was separated, washed with water, brine,dried and concentrated to give crude product, which was purified bycolumn chromatography, using 20% EtOAc in hexane to give 775 mg of4-(benzo[b][1,4]dioxin-2-yl)phenyl acetate (62%). MS (ES) m/z: 269.92(M+1), 268.91 (M); Mp. 123-125° C.

Example 78

4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoatetetrahydrochloride

HCl (0.4 mL, 2 N) was added to 4-isoquinolin-3-yl-phenol (0.133 g, 0.6mmol) in anhydrous DMF (5 mL). To this mixture were added HOBt (0.081 g,0.6 mmol), Boc-Arg-(Boc)₂-OH (0.285 g, 0.6 mmol), and EDCl (0.115 g, 0.6mmol). N,N-Diisopropylethylamine (0.233 g, 1.8 mmol) was added and themixture was stirred at rt for 24 h. Water (15 mL) was added and thewhite precipitate was filtered off, washed with water and dried undervacuum to give 0.3 g (74%) of the Boc-arginine derivative. The Bocderivative compound (0.3 g,) was dissolved in anhydrous dichloromethane(10 mL). HCl gas was bubbled into the solution at 0° C. for 4 h. Ayellow precipitate was formed. The solvent was removed and the resultingsold was dried under vacuum. Triturating with ether gave 200 mg of4-(isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoatetetrahydrochloride (86%). MS (ES) m/z: 222.96 (M+1-Arg), 221.99 (M-Arg);Mp. 198-201° C.

Example 79

4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl2-amino-5-guanidinopentanoate trihydrochloride

3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one (150 mg, 0.63 mmol) in DMF (5mL), diisopropyl ethyl amine (245 mg, 1.89 mmol), EDCl (133 mg, 0.696mmol), Boc-arginine (330 mg, 0.696 mmol) and HOBt (94 mg, 0.696 mmol)were stirred and stirred at rt for 24 h under nitrogen. The reactionmixture was diluted with water and the solid was collected byfiltration. The solid was purified by column chromatography using 5%MeOH in DCM to give the tri-Boc ester product (375 mg 85%). HCl gas wasbubbled through a solution of the tri-Boc ester (325 mg, 0.468 mmol) inDCM (10 mL) for 6 h at 0° C. The solid was filtered off and washed withDCM to give 170 mg of 4-(1-oxo-1,2-dihydroisoquinolin-3-yl)phenyl2-amino-5-guanidinopentanoate trihydrochloride (72%). MS (ES) m/z:237.25 (M-Arg); ¹³C-NMR (DMSO-d₆): δ168.8, 163.4, 157.7, 151.0, 139.8,139.5, 133.4, 132.8, 128.9, 127.4, 127.3, 127.25, 125.6, 122.6, 104.2,55.6, 52.5, 27.7, 25.0.

Example 80

2-(4-Nitrophenyl)-4H-pyrano[2,3-b]pyridine-4-one

To a stirred solution of 2-methoxynicotinic acid (2.3 g, 15 mmol) in 75mL anhydrous THF was added N-methyl morpholine (1.52 g, 15 mmol). Thereaction mixture was cooled to −10° C. Ethylchloroformate (1.63 g, 15mmol) was added dropwise at −10° C. The reaction mixture was stirred at−10° C. for 15 min. and then at rt for 10 h. Water (50 mL) was added,and the solution was extracted with ethyl acetate. The organic layer wasseparated, dried (Na₂SO₄), and concentrated to give a colorless liquidin 97% yield (3.29 g). To a solution of this colorless liquid (3.28 g,14.57 mmol) and 4′-nitroacetophenone (2.477 g, 15 mmol) in anhydrous THF(75 mL) was added lithium bis(trimethylsilyl)amide 1.0M solution in THF(18 mL) at −30° C. over a period of 45 min. Stirring continued at −30°C. for 30 min. The reaction mixture was allowed to warm to rt. Thestirring was continued for another 15 h at rt, and the reaction mixturewas then diluted with ethyl acetate (200 mL). Saturated NH₄Cl solution(50 mL) was added. The organic layer was separated and dried overanhydrous Na₂SO₄. Removal of solvent gave the crude product which wastriturated with ether to give 1-(2-methoxypyridine-3-yl)-3-(4-nitrophenyl)propane-1,3-dione as yellow solid in 62%yield (2.79 g).

1-(2-methoxy pyridine-3-yl)-3-(4-nitrophenyl) propane-1,3-dione (2.16 g,7.193 mmol) and pyridinium hydrochloride (12.47 g, 107.9 mmol) weremixed together and stirred at 190° C. for 2 h under nitrogen atmosphere.The reaction mixture was cooled to rt. Water (100 mL) was added, thesolid was separated by filtration, washed with water and dried undervacuum. The crude compound was purified by column chromatography(SilicaGel 230-400 mesh; 2-5% methanol in CH₂Cl₂ as eluent) to give2-(4-nitrophenyl)-4H-pyrano[2,3-b]pyridine-4-one as a brown solid in 43%yield (0.82 g). MS (ES) m/z: 268.88 (M); Mp. 261-263° C.

Example 81

2-(4-Hydroxy-3-(hydroxymethyl)phenyl)-4H-pyrano[2,3]-b]pyridine-4-one

2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one (0.91 g,0.0036 mol), acetic anhydride (1.2 g, 0.0117 mol), DMAP (0.05 g) andtriethylamine (10 mL) were added to a 50 ml flask and stirred overnightat rt. The solvent was removed and ethyl acetate (100 mL) was added andwashed with water (80 mL), brine and dried over sodium sulfate. Afterthe majority of the ethyl acetate was removed, hexane was added and thesolid was isolated by filtration to give the acetylated intermediate(0.978 g, 92.0%).

The acetylated intermediate (0.50 g, 0.0017 mol) was dissolved into drycarbon tetrachloride (20 mL) and NBS (0.317 g, 0.00178 mol) was added.The reaction mixture was heated to reflux under a lamp for 3 h. Aftercooling the solid was filtered off and further washed with hot water toremove the succinimide. The methyl bromide was isolated bycrystallization from DCM/Hexane (0.497 g, 78.2%).

The methyl bromide (0.49 g (0.0013 mol) and sodium acetate (1.07 g,0.0131 mol) were mixed in acetic acid (20 mL) and heated to reflux for16 hours. Acetic acid was removed and the residue was poured into waterand extracted with ethyl acetate. The organic layer was washed withwater, brine and dried in sodium sulfate. The solvent was removed and0.50 g of the crude diacetylated compound was isolated. The diacetylatedcompound (0.50 g), potassium carbonate (0.45 g), and methanol (10 mL)were mixed and stirred for 3 hours. Acetic acid (2 mL) was added and thepH was adjusted to 5. The organic solvent was removed and the crudemixture was purified by column chromatography (DCM:MeOH 20:1) and thenrecrystallized to give2-(4-hydroxy-3-(hydroxymethyl)phenyl)-4H-pyrano[3,2-b]pyridine-4-one (70mg, 19.8%). MS (ES) m/z: 269.92 (M); Mp. 226-227° C.

Example 82

4-(6,8-Dimethoxy-1-(methylamino)isoquinolin-3-yl)phenol hydrochloride

To a suspension of 2-methyl-4,6-dimethoxy benzoic acid (2.8 g, 14.27mmol) in CH₂Cl₂ (30 mL), oxalyl chloride (3.62 g, 28.54 mmol) was addedand the mixture was stirred at rt for 16 h. The solvent and excess ofoxalyl chloride were removed at reduced pressure. The solid wasdissolved in CH₂Cl₂ (10 mL) and methyl amine hydrochloride (1.33 g,42.81 mmol) was added on cooling and the mixture was stirred at rt for 4h. The solvent was removed and the crude product was purified bychromatography by using 5% methanol in CH₂Cl₂, to give 1.3 g of theamide intermediate in 43% yield.

To a solution of the amide intermediate (1.29 g, 6.16 mmol) in THF (30mL) under N₂ was slowly added n-butyl lithium (5.6 mL, 14.18 mmol, 2.5 Msolution in hexane) with cooling (ice-salt bath), maintaining thetemperature below 20° C. The mixture was stirred for 1 h at 0° C., thencooled to −50° C. and a solution of 4-O-TBDMS-benzonitrile (1.58 g, 6.78mmol) in THF (10 mL) was added quickly. The cooling bath was removed andallowed to warm to rt and stirred for 16 h at rt. Saturated aqueousNH₄Cl solution was added with cooling, and the layers were separated.The organic layer was washed with water, brine, dried over Na₂SO₄ andconcentrated to give the crude intermediate, which was purified bychromatography using 5% methanol in CH₂Cl₂, to give two products: (1)678 mg of isoquinoline in 26% yield and (2) 780 mg of quinalone productin 27% yield.

To a suspension of the isoquinoline (678 mg, 1.59 mmol) in ethanol (20mL), conc. HCl (2 mL) was added and the mixture was heated at 80° C. for2 h. The reaction mixture was cooled to rt, solvent was removed and thesolid was washed well with ethyl acetate to give4-(6,8-dimethoxy-1-(methylamino)isoquinolin-3-yl)phenol hydrochloride(445 mg, 80%). MS (ES) m/z: 312.04 (M+1); Mp. 250-253° C.

Example 83

7-Hydroxy-3-(4-hydroxyphenyl)-chromen-4-one

In a solution of 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (2mmol) in DMF (6 mL), freshly destilled BF₃.OEt₂ (6.3 mL) was added underargon. The mixture was heated at 50° C., and a solution ofmethanesulphonyl chloride (1 mL) in dry DMF (1.5 mL) was added slowly.After reaction at 80° C. for 1 h, the mixture was cooled to rt andpoured into a large volume of ice cold aq. sodium acetate (12 g/100 mL),then extracted with EtOAc, and the organic layer was dried andconcentrated. The residue was purified by column chromatography onsilica gel using a mixture of DCM and MeOH to give7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one.

Example 84

3-(4-Hydroxyphenyl)-4H-chromen-4-one

To a mixture of 3-bromochromone (1.5 g, 6.66 mmol), 4-methoxy phenylboronic acid (1.01 g, 6.66 mmol), sodium carbonate (2.12 g, 20.0 mmol),toluene (40 mL) and water (10 mL) was added tetrakis-triphenyl phosphinepalladium (385 mg, 0.33 mmol) under N₂. The reaction mixture was heatedto 110° C. for 5 h and then cooled to rt. Water was added and themixture was extracted with EtOAc. The organic layer was separated,washed with water, brine, dried and concentrated to give crude product,which was purified by column chromatography, using 20% EtOAc in hexaneto give, 885 mg of 4′-methoxychromone product in 52% yield. A mixture ofthe above mentioned 4′-methoxychromone (400 mg, 1.58 mmol) andpyridinium hydrochloride (5 g) was heated at 190° C. for 4 h. Thereaction mixture was cooled to rt, diluted with water, neutralized withNaHCO₃ and filtered to give 314 mg of3-(4-hydroxyphenyl)-4H-chromen-4-one (83%). MS (ES) m/z: 239.95 (M+1),238.99 (M); Mp. 237-238° C.

Example 85

3-(4-Hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one

Methyl 4-methoxyphenylacetate (5.58 g, 0.031 mol) was added to anhydroustoluene (75 mL) and the reaction mixture was kept at −70° C.Diisobutylaluminum hydride (1.0 M, 34 mL) in toluene was added over 25min. The reaction mixture was stirred for another 20 min then asodium-potassium-tartrate solution (100 mL) was added to the reactionmixture. The organic layer was separated and the water layer wasextracted with ether. The combined organic layers were washed withwater, brine, and dried over sodium sulfate. The crude compound waspurified by column chromatography (hexane:EtOAc 4:1) to yield4-methoxyphenylacetaldehyde (0.90 g, 19.3%). A mixture of4-methoxyphenylacetaldehyde (0.40 g, 2.66 mmol), morpholine (0.232 g,2.66 mmol), and benzotriazole (0.304 g, 2.56 mmol) in ether (20 mL) with3 Å molecular sieves was stirred at rt overnight. The molecular sieveswere removed by filtration and the solvent was removed. The crudeproduct was used for next step reaction without further purification.Sodium hydride (0.125 g, 5.2 mmol, 60% in mineral oil) was added to thecrude product with anhydrous THF (20 mL). The reaction mixture wasstirred at reflux for 3 h. THF was removed and the residue was pouredinto cold water (60 mL) and extracted with hexane (2×80 mL). The organiclayer was dried over sodium sulfate and the solvent was removed to givethe enamine (0.60 g). 2-Chloropyridine-3-carbonylchloride (0.44 g, 2.5mmol) in dry DCM (5 mL) was added to the enamine (0.60 g), followed bytriethylamine (0.5 mL) in anhydrous DCM (15 mL) at −70° C. The reactionmixture was allowed to warm to rt overnight. The mixture was then pouredinto water, and the organic phase was washed with sodium bicarbonate andbrine. The crude residue was purified by column chromatography(EtOAc:MeOH 5:1) to the desired intermediate (0.45 g). The intermediate(0.45 g, 1.25 mmol) was stirred in HCl (8.0 mL, 6 N) overnight at rt.The desired compound was filtered off and washed with large amounts ofwater. The crude product (0.24 g, 1.18 mmol) was mixed with pyridinehydrochloride (1.4 g) and heated to 180-190° C. for 3 h. The mixture waspoured into water and stirred for 30 min. The solid was filtered off andfurther washed with water and hexane to give 140 mg of3-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (49.6%). MS (ES) m/z:239.90; Mp. 262-264° C.

Example 86 ApoA-I Promoter Induction in Caco-2 Intestinal Cells

To examine the effects of compounds of the invention to increase ApoA-Iexpression, Caco-2 cells, an intestinal cell line derived from humanepithelial intestinal cells, were grown under conditions recommended bythe ATCC and summarized in United States Patent Application PublicationNo. 20040033480 (“Wong”), incorporated herein by reference. Wongdemonstrates that resveratrol increases ApoA-I promoter activity by2.5-times over untreated control. This study similarly demonstrates thatcompounds of the present invention induce ApoA-I promoter activity.

Briefly, the promoter region of the gene encoding human ApoA-I wasisolated and ligated upstream of the firefly luciferase gene toconstruct the reporter plasmid pAI.474-Luc. This reporter plasmid andpRSV-β-galactosidase (as a control for transfection efficiency) wereco-transfected to Caco-2 cells. The Caco-2 cells were then incubated ina MEM selection media containing 20% fetal calf serum supplemented withG418 (final concentration: 0.5 mg/mL, Gibco) to give established strainsthat stably express from the reporter gene. The strains were seeded in6-well culture plates and incubated for 48 hours at 37° C. under 5%carbon dioxide. Cells were starved for 24 hrs in MEM selection mediacontaining 0.5% FBS. Then, a solution of a compound of the invention inDMSO or other appropriate solvent was added to the wells at a finalconcentration of 0 to 100 μM in MEM selection media containing 0.5% FBS.

After further incubation for 48 hours, the cells were harvested andlysed using Reporter Lysis Buffer (PROMEGA E3971), and 50 μL ofluciferase assay reagent (PROMEGA E4550 Luciferase Reporter 1000 assaysystem) was added to measure luciferase activity with a luminometer(Fluoroskan Ascent FL from Thermo electron Corporation). Luciferaseactivity was normalized to lysate protein concentrations, measured usingBradford Reagent (BioRad Protein Assay reagent Cat#500-0006). Theluciferase activity of cells treated with various concentrations of testcompounds was compared to that of solvent control sample (i.e., solventwithout any compound of the present invention added) and untreatedcontrol sample. An increase in luciferase activity compared to controlsamples indicated that the compound of the invention increased theexpression of ApoA-I. The results provided in Table 2 are based onvalues obtained at 15 μM concentrations.

TABLE 2 Induction of ApoA-I Promoter in Caco-2 Intestinal Cells ApoA-IPromoter Compound Induction Resveratrol increased5,7-Dihydroxy-2-(4-hydroxyphenyl)-chroman-4-one increased5,7-Dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one increased5,7-Dihydroxy-2-phenyl-4H-chromen-4-one increased5-Hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one increased7-Hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one increased5-Hydroxy-2-phenyl-4H-chromen-4-one increased2-(4-Hydroxyphenyl)-chromen-4-one increased7-Hydroxy-2-phenyl-4H-chromen-4-one increased 2-Phenyl-4H-chromen-4-oneincreased 6-Hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one increased2-(3-Hydroxyphenyl)-4H-chromen-4-one increased2-(4-Hydroxy-3-methoxyphenyl)-4H-chromen-4-one increased4-(4-Oxo-4H-chromen-2-yl)-phenyl nicotinate (Example 71) increased2-(4-Nicotinoyloxy)phenyl)-oxo-4H-chromene-5,7-diyl increaseddinicotinate (Example 74)5,7-Difluoro-2-(4-hydroxyphenyl)-4H-chromen-4-one increased (Example 2)5,7-Difluoro-2-(4-methoxy-phenyl)-chromen-4-one no increase (Example 1)2-(4-Hydroxy-phenyl)-1H-quinolin-4-one (Example 51) no increase2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one increased (Example 34)2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one increase (Example 35)2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one (Example 46) increased4-(4-Oxo-4H-chromen-2-yl)phenyl acetate (Example 72) increased2-Pyridin-4-yl-chromen-4-one (Example 47) increased4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate increased (Example75) 2-(6-Hydroxypyridin-3-yl)chromen-4-one (Example 48) no increase2-(4-Hydroxyphenyl)-pyrano[2,3-c]pyridin-4-one increased (Example 36)2-(4-Hydroxyphenyl)-4H-pyrano[3,2-c]pyridin-4-one increased (Example 39)3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one (Example 53) increased4-Isoquinolin-3-yl-phenol (Example 54) increased4-(1,6-Naphthyridin-7-yl)phenol (Example 57) increased2-Amino-5-guanidino-pentanoic acid 4-(4-oxo-4H- increasedchromen-2-yl)phenyl ester trihydrochloride (Example 76)4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate (Example 77) increased2-(4-Methoxy-phenyl)-4H-chromen-4-one (Example 4) increased8-Hydroxy-2-(4-hydroxy-phenyl)-4H-chromen-4-one increased (Example 5)2-(4-Hydroxy-3,5-dimethylphenyl)chromen-4-one increased (Example 7)4-Naphthalen-2-yl-phenol (Example 65) increased2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one increased(Example 37) 2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one increased(Example 17) 2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-oneincreased (Example 18)2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine- increased 4-one(Example 41) 2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-c]pyridine 7- noincrease oxide (Example 30) 2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-oneincreased (Example 19) 4-(Isoquinolin-3-yl)phenyl2-amino-5-guanidinopentanoate increased tetrahydrochloride (Example 78)3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin- increased 1(2H)-one(Example 59) 3-(4-Hydroxyphenyl)-6,8-dimethoxyisoquinolin-3-yl)phenolincreased hydrochloride (Example 60)4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile increased (Example40) 3-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H- no increasechromen-4-one hydrochloride (Example 20)4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl 2-amino-5- increasedguanidinopentanoate trihydrochloride (Example 79)2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[2,3-b]pyridine 8- no increase oxide(Example 31) 7-(3-Fluoro-4-hydroxyphenyl)-6-methyl-1,6-naphthyridin- noincrease 5(6H)-one (Example 56)4-(6-Bromo-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate increased(Example 25) 2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrileincreased (Example 21)2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin- increased 4-one(Example 42) 5,7-Dihydroxy-2-(4-hydroxyphenyl)-quinolin-4(1H)-oneincreased (Example 50)2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine- increased 4-one(Example 45) 2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-oneincreased (Example 44)2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one increased(Example 26) 2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-increased 4-one (Example 43)2-(4-Nitrophenyl)-4H-pyrano[2,3-b]pyridin-4-one no increase (Example 80)2-(4-Hydroxyphenyl)-4-oxo-4H-pyrano[3,2-c]pyridine 6- no increase oxide(Example 32) 2-(4-Hydroxy-3-(hydroxymethyl)phenyl)-4H-pyrano[2,3-increased b]pyridin-4-one (Example 81)4-(Benzo[b][1,4]dioxin-2-yl)phenol (Example 70) increased2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one (Example 67) increased4-(4,4-Dimethyl-4H-chromen-2-yl)phenyl acetate increased (Example 69)2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine- increased 4-one(Example 38) 2-(3-Fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H-increased chromen-4-one (Example 33)4-(6,8-Dimethoxy-1-(methylamino)isoquinolin-3-yl)phenol increasedhydrochloride (Example 82)3-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one increased (Example85) 5,7-Dihydroxy-3-(4-hydroxyphenyl)-chromen-4-one increased3-(4-Hydroxyphenyl)-4H-chromen-4-one (Example 84) increased

The results of these assays indicate that an electron donating group inthe “B”-ring, in particular the 4′ position, following the flavonoidnomenclature, or R7 position in Formula I and IV, generally improvesApoA-I promoter activity. For example, a comparison of the results of5-hydroxy-2-phenyl-4H-chromen-4-one to5-hydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one demonstrated that the 4′hydroxyl plays a role in the increase in ApoA-I promoter activity. Thesestudies further demonstrated that a nitrogen atom in the “A”-ring,following the flavonoid nomenclature of Formula I and IV, does notsuppress the activity of the 4′ hydroxyflavone; however, the nitrogenatom does improve the pharmacokinetic properties, for example,increasing the solubility as discussed below in connection with thesolubility assays. Unexpectedly, the presence of an oxygen in the C1position and nitrogen in the 8 position improves ApoA-I promoteractivity. The presence of a carbon at position C1 and nitrogen in the 3and/or 8 positions also appears to enhance ApoA-I promoter activity.

Example 87 Kinetics of ApoA-I Promoter Induction

Whereas the preceding studies showed that the compounds of the inventionstimulate ApoA-I promoter activity, the duration of action was unclear.Accordingly, the kinetics of induction of the ApoA-I promoter wereassessed.

Caco-2 cells transfected with pAI.474-Luc were treated with compounds ofthe invention at selected time points varying from 4 to 72 hours. Thisconstruct pAI.474-Luc contained the human ApoA-I promoter fused to thereporter gene, firefly luciferase (Luc). Wong demonstrated that when thetest compound is resveratrol a significant stimulation of ApoA-Ipromoter activity in Caco-2 cells was observed at 4, 8, 16 and 24 hoursfollowing administration, but maximal stimulation was observed following16 hours of exposure.

5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one was found to have asignificant effect on ApoA-I promoter activity at 16, 24, 28 and 72hours following its administration. Further, maximal stimulationappeared following 48 hour exposure. 4′-hydroxyflavone had a significanteffect on stimulation of ApoA-I promoter activity in Caco-2 cells at 16,24, and 48 hours following the administration. Maximal stimulationappeared following 48 hour exposure to the compound.

Example 88 Confirmation of ApoA-I Induction in Caco-2 Intestinal Cells

This experiment will measure the ability of a test compound to stimulatetranscriptional activity of the endogenous Apo-A1 promoter in the Caco-2cells. Such simulation will result in an increase in expression ofApoA-I protein, which is ultimately responsible for antiatherogenicactivity. A test compound, such as, for example,5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one, which hasdemonstrated an increase in the activity of the ApoA-I promoter in thepAI.474-Luc construct, may be tested in this assay to confirm its effecton the activity of the ApoA-I gene endogenous to the Caco-2 cells. TheCaco-2 cells are cultured as described in Wong and exposed to mediacontaining 5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one or othertest compound at a concentration of 5, 7.5, 10, 15 or 20 μM for 24 or 48hours. Longer exposure of the cells to the test compound is utilized toallow adequate time for the ApoA-I protein to be secreted into the mediafrom the Caco-2 cells, and detected. Conditioned media exposed to thecells for 24 or 48 hours is assayed for its content of ApoA-I proteinusing Western blot analysis and enzyme-linked immunoassay (ELISA).

Results should show an increase in the amount of ApoA-I protein in theconditioned media from cells treated with test compound as compared tountreated cells. The results of these studies will demonstrate that atest compound augments expression of the ApoA-I gene and is, therefore,antiatherogenic. Increased expression of the ApoA-I gene augmentsreverse cholesterol transport and thereby facilitates the removal ofcholesterol from the body.

Example 89 ApoA-I Promoter Induction in HepG2 Liver Cells

This study determined whether compounds of the invention have an effecton ApoA-I promoter activity expression in HepG2 cells, a liver cellline. Cells were grown under conditions recommended by the ATCC andsummarized by Wong.

The promoter region of the gene encoding human ApoA-I was isolated andligated upstream the structure gene of firefly luciferase to construct areporter plasmid (pAI.474-Luc). The reporter plasmid, along withpRSV-β-galactosidase (as a control for transfection efficiency), wereco-transfected into HepG2 cells. The cells were then incubated in an MEMselection media containing 20% fetal calf serum supplemented with G418(final concentration: 0.5 mg/mL, Gibco) to give established strains thatstably express from the reporter gene. The strains were seeded to a6-well culture plates and incubated for 48 hours at 37° C. under 5%carbon dioxide. Cells were starved for 24 hrs in MEM selection mediacontaining 0.5% FBS. Then, a solution of the compounds of the inventionin DMSO (or other appropriate solvent) was added to the wells at a finalconcentration of 0 to 100 μM in MEM selection media containing 0.5% FBS.

After further incubation for 48 hours, the cells were harvested andlysed using Reporter Lysis Buffer (PROMEGA E3971), and 50 μL ofluciferase assay reagent (PROMEGA E4550 Luciferase Reporter 1000 assaysystem) were added to measure luciferase activity with a luminometer(Fluoroskan Ascent FL from Thermo electron Corporation). Luciferaseactivity was normalized to lysate protein concentrations, measured usingBradford Reagent (Biorad Protein Assay reagent Cat#500-0006). Anincrease in luciferase activity compared to untreated and or controlsamples indicates that the compound of the invention increases theexpression of ApoA-I. The results provided in Table 3 are based onaverage values at 15 μM concentrations.

TABLE 3 Induction of ApoA-I Promoter in HepG2 liver cells ApoA-IPromoter Compound Induction6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one increased (Example 14)4′,5-dihydroxyflavone increased5,7-dihydroxy-2-(4-hydroxyphenyl)-chroman-4-one increased3,5,7-trihydroxy-2-(3,4-dihydroxyphenyl)-chromen-4-one increased5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chomen-4-one increased2-(4-(nicotinoyloxy)phenyl)-4-oxochroman-5,7-diyl no dinicotinate(Example 73) increase2-(4-nicotinoyloxy)phenyl)-oxo-4H-chromene-5,7-diyl increaseddinicotinate (Example 74) 4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate(Example 71) increased 2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-oneincreased (Example 34) 2-(2-amino-4-hydroxy-phenyl)-chromen-4-one(Example 3) increased 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (Example53) increased 4-isoquinolin-3-yl-phenol (Example 54) increased6-hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one increased (Example 11)2-(3-fluoro-4-hydroxyphenyl)chromen-4-one (Example 12) increased4′-hydroxyflavone increased

Example 90 ApoA-I Protein Expression in HepG2 Cells

This study confirmed that compounds of the invention have an effect onApoA-I protein secretion in HepG2 (liver) cells by measuring whetherstimulation of transcriptional activity of the endogenous ApoA-Ipromoter in the HepG2 cells increased the abundance and secretion ofApoA-I protein.

The HepG2 cell line was obtained from the ATCC and cultured in MEM mediasupplemented with 10% FBS (Gibco), with 1 mM sodium pyruvate, 0.1 mM MEMnon-essential amino acid, 2 mM L-glutamine, 100 U/ml penicillin, 100μg/ml streptomycin and 5 μg/ml plasmocin. Cells were maintained at 37°C. in an atmosphere of 5% CO₂ Cells were grown to 85% confluency priorto initiating the experiment.

Cells were plated and allowed to adhere overnight in a phenol red-freeDMEM containing 10% of Charcoal/Dextran treated FBS (Hyclone), with 1 mMsodium pyruvate, 0.1 mM MEM non-essential amino acid, 2 mM L-glutamine,100 U/ml penicillin, 100 μg/ml streptomycin and 5 μg/ml plasmocin. Themedium was removed, and cells were washed in 1×PBS. Cells were thenstarved in phenol red-free DMEM (serum free) for a period of 24 hours.Cells were then mock treated (untreated, DMSO), or treated with compoundof the invention diluted in phenol red-free DMEM (serum free) media at aconcentration of 7.5 μM. Cells and media were harvested at 0, 6 and 24hours following compound treatment.

Medium was removed from cells at the desired times and applied to asolid phase capture sandwich in an ELISA assay according tomanufacturer's instructions (Total human Apolipoprotein ELISAAssay—Alercheck). FIG. 1 shows results from an ELISA analysis to measureApoA-I protein content from conditioned media from HepG2 Cellsuntreated, treated with diluent and treated with compound at 0, 6 and 24hours after exposure. When HepG2 cells were treated for 6 and 24 hourswith compound 2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (Example34), 2-(4-hydroxyphenyl)-3-methyl-4H-chromen-4-one (Example 24),4-(1,6-naphthyridin-7-yl)phenol (Example 57) and2-(4-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (Example 44), theApoA-I content in the medium increased significantly when compared withuntreated cells and cells treated with solvent.

While not wishing to be limited to a theory, the time course experimentindicates that the rate at which ApoA-I levels increase in the medium ofHepG2 cells treated with 2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one(Example 34), 2-(4-hydroxyphenyl)-3-methyl-4H-chromen-4-one (Example24), 4-(1,6-naphthyridin-7-yl)phenol (Example 57) and2-(4-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (Example 44) isstarting at ˜6 hours after the addition of compound to the medium. Thismay suggest that the mechanism responsible for the increase in ApoA-Iproduction by hepatic cells involves the induction of the ApoA-I gene atthe transcriptional level.

Accordingly, representative compounds of the invention activate promoteractivity for ApoA-I, leading to an increase in transcription, asdemonstrated in Example 86 and 89 and increase in synthesis of ApoA-I,as demonstrated in Example 90. Thus, the compounds of the invention andpharmaceutically acceptable salt or hydrate thereof, can be expected toelevate ApoA-I protein expression level, in intestinal and liver cellsand be useful for elevating plasma ApoA-I levels in a patient to whomthe compounds are administered.

Example 91 Solubility Analysis

To evaluate the solubility of illustrative compounds of the invention, 1mg of compound was added to 1 mL of PBS and sonicated for 1 hour at roomtemperature using the Branson 3210 Sonicator in triplicate and incubatedin a water bath at 25° C. for 3 hrs. Samples were then centrifuged at14,000 rpm for 6 minutes at room temperature. The supernatant wasdiluted with acetonitrile and was removed for analysis. Analysis wasperformed using HPLC-UV with 7-point standard curve to determine theconcentration. The average concentration calculated is regarded as thesolubility (μM). Table 4 shows the results of these experiments.

TABLE 4 Solubility Analysis Solubility Compound (PBS) (μM)5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chomen-4-one 3.37*3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (Example 44.89 53)4-(6,8-dimethoxy-1-(methylamino)isoquinolin-3- 66.83 yl)phenolhydrochloride (Example 82)2-(4-hydroxyphenyl)-4H-pyrano[3,2-c]pyridine-4-one 31.60 (Example 39)4′-hydroxyflavone 5.042-(3-chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine- 84.37 4-one(Example 41) 2-(3-bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin- 52.594-one (Example 42) 2-(3-fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-194.50 one (Example 37) 3-(4-Hydroxyphenyl)-6,8-dimethoxyisoquinolin-1(2H)- 58.24 one (Example60)2-(4-hydroxy-3-methoxyphenyl)-4H-pyrano[2,3- 47.09 b]pyridine-4-one(Example 43) 2-(4-(2-hydroxyethoxy)phenyl)-4H-pyrano[2,3- 334.05b]pyridine-4-one (Example 45)2-(4-hydroxy-3-(hydroxymethyl)phenyl)-4H-pyrano[2,3- 48.54b]pyridin-4-one (Example 81)2-(3-fluoro-4-hydroxyphenyl)-6-(hydroxymethyl)-4H- 51.42 chromen-4-one(Example 33) *S. P. Ng et al., “Evaluation of the first-passglucoronidation of select flavones in the gut by Caco2 monolayer model,”J. Pharm. Pharmaceut. Sci. 8(1): 1-9 (2005)

These experiments indicate that the solubility of representativecompounds of the invention is significantly better than that ofnaturally occurring polyphenols, such as apigenin with a solubility of3.27 μM. The poor bioavailability of naturally occurring polyphenols ispartially attributed to poor solubility. As such, solubility is unlikelyto affect the validity of any in vitro tests performed on the compoundsof the invention, and formulation of these compounds for in vivo workshould not be technically difficult to one skilled in the art.Accordingly, the compounds of the invention and pharmaceuticallyacceptable salts and hydrates thereof, are suitable for human use due tothe unexpected utility of improved solubility.

Example 92 Caco-2 Permeability

The Caco-2 cell drug transport model is widely used for screeningcompounds in drug discovery to assess intestinal transport and predictabsorption rates. For example, the fraction of drug absorbed in humancould be determined by in vivo human permeability or predicted by invitro Caco-2 permeability; if compound permeability in Caco-2 cellsreaches 13.3-18.1×10⁻⁶ cm/s, it is predicted that in vivo, permeabilityin humans would reach 2×10⁻⁴ cm/s, and the predicted fraction of drugabsorbed would be >90%, which is defined as highly permeable. (D. Sun etal., “In vitro testing of drug absorption for drug ‘developability’assessment: forming an interface between in vitro preclinical data andclinical outcome,” Curr. Opin. Drug Discov. Devel. 7(1):75-85 (2004).Therefore, in vitro absorption testing is a highly valuable tool forcomparison of structural analogues for improved intestinal absorption,and to identify compounds within the decision-making process forclinical studies at early-stage drug discovery and development.

The method of B. Hai-Zhi et al., “High-throughput Caco-2 cellpermeability screening by cassette dosing and sample pooling approachesusing direct injection/on-line guard cartridge extraction/tandem massspectrometry,” Rapid Communications in Mass Spectrometry 14:523-528(2000) may be used with obvious modifications to someone skilled in theart. FIG. 2 and Table 5 show the results of permeability ofrepresentative compounds of the invention in an in vitro Caco-2intestinal transport model over time, and compared to resveratrol and5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (apigenin).

TABLE 5 Permeability Analysis % Transported Compound Paap (cm/s)Propanol 1.01 × 10⁻⁵ 2-(2-amino-4-hydroxy-phenyl)-chromen-4-one (Example3) 7.42 × 10⁻⁶ 7-methoxy-2-(4-hydroxyphenyl)-4H-chromen-4-one 6.92 ×10⁻⁶ 2-pyridin-4-yl-chromen-4-one (Example 47) 6.48 × 10⁻⁶2-(4-hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one 6.36 × 10⁻⁶ (Example 34)4-(1,6-naphthyridin-7-yl)phenol (Example 57) 5.34 × 10⁻⁶4′-hydroxyflavone 4.31 × 10⁻⁶ 4-isoquinolin-3-yl-phenol (Example 54)4.11 × 10⁻⁶ Resveratrol 3.34 × 10⁻⁶ 4-(4-oxo-4H-chromen-2-yl)phenylacetate (Example 72) 2.65 × 10⁻⁶2-(3-fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one 2.06 × 10⁻⁶(Example 37) 2-(4-hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one 1.98 × 10⁻⁶(Example 35) 3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (Example 53) 1.76× 10⁻⁶ 2-(3-chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine- 1.76 ×10⁻⁶ 4-one (Example 41)5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chomen-4-one 1.50 × 10⁻⁶2-(5-hydroxy-pyridin-2-yl)-chromen-4-one (Example 46) 1.23 × 10⁻⁶2-(4-hydroxyphenyl)-4H-pyrano[3,2-c]pyridine-4-one 1.21 × 10⁻⁶ (Example39) 2-(3-bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin- 9.59 × 10⁻⁷4-one (Example 42) 2-(4-hydroxy-3,5-dimethylphenyl)chromen-4-one 6.95 ×10⁻⁷ (Example 7) 2-(4-hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-5.96 × 10⁻⁷ 4-one (Example 38)2-(3,5-difluoro-4-hydroxyphenyl)chromen-4-one 5.31 × 10⁻⁷ (Example 6)5,7-dihydroxy-2-phenyl-4H-chromen-4-one 1.22 × 10⁻⁷

These experiments indicate that the permeability of representativecompounds of the invention are equivalent to or greater than naturallyoccurring polyphenols, such as5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-chromen-4-one (apigenin) with apermeability of 1.50×10⁻⁶ or resveratrol with a permeability 3.34×10⁻⁶.Accordingly, the compounds of the invention and pharmaceuticallyacceptable salts and hydrates thereof, are potentially suitable forhuman use due to the permeability of intestinal cells to thesecompounds.

Example 93 Transgenic Mice

To test whether the efficacy of compounds of the invention observed invitro extended to an in vivo model, transgenic mice carrying multiplecopies of the human ApoA-I gene (C57BI/6-tgn(apoa1)1rub, JacksonLaboratory, Bar Harbor, Me.) were exposed to representative compounds ofthe invention. The exogenous human ApoA-I gene in these mice enablesthem to express the human ApoA-I protein under the control of thispromoter.

Seven to eight week old male mice, transgenic for human ApoA-I werehoused five per cage (10″×20″×8″ with aspen chip bedding) with pelletedRodent chow [Purina 5001] and water available at all times. After anacclimation period of 1 week, animals were individually identified bynumbering on tail and weighed. Mice were pre bled via the retro-orbitalplexus, and 150 μl of blood was collected in 1.5 ml Eppendorf tubecontaining 1 μl of heparin and chilled on ice. Plasma was collectedafter centrifuging the whole blood at 14000 rpm [TOMY high speedmicro-refrigerated centrifuge NTX-150] for 10 minutes at 4° C. andfrozen at −80° C. Plasma was analyzed for: human ApoA-I by a humanApoA-I enzyme-linked Immunoassay [Direct Sandwich ELISA CalbiochemCat#178422, Calbiochem Cat#178452, lot #B9076, Calbiochem Cat #178470conjugated to Horse Radish Peroxidase (Cedarlane Cat#80220)]; totalcholesterol [Ponte scientific reagents: # C7509-STD, #L7580-18, #C7510]; and triglyceride [Pointe Scientific Reagents: #7532-STD,#L7580-18, #7532]. All samples were measured in triplicates andexpressed as mg/dl. Mice were grouped based on the above plasmaparameters and having an average body weight of 25 gm.

Two days following pre-bleed, mice were dosed by oral gavage daily for14 days using a 20 gauge, 1½″ curved disposable feeding needle [Popper &Sons]; when BID, mice were gavaged morning and afternoon (8 am and 5pm); when SID mice were gavaged in morning (8 am). Compounds wereprepared each day in vehicle. Test article(s), a positive controlfenofibrate, and vehicle were dosed at volume of 5 mL/kg of body weightas a suspension (0.1 mL/20 g mouse). Fenofibrate was obtainedcommercially [SIGMA #F 6020]. Mice weights were recorded on day 1, 4, 7,10, 12, and 15. On day 15, mice were weighed and fasted for 4 hours,sacrificed by inhalation of CO₂ and blood was obtained via cardiacpuncture (0.7-1.0 ml). Plasma was collected and frozen at −80° C.Samples were assayed for ApoA-I, total cholesterol, triglyceride andHDL-C by HPLC [Polaris 200 with an auto sampler Prostar 410 from Varianon a Superose 6 10/30 column from Amersham]. Samples were sent for NMRanalysis [LipoScience] to identify particle size and subclass forlipoproteins. During necropsy, liver, brown fat, and the whole of smalland large intestines were collected, cleaned with cold PBS and frozen at−80° C. for further analysis of compound levels. Variation betweenstudies, in ApoA-I changes, was observed. Therefore, a relativecomparison between individual(s) in the study groups was used.

Experiment A

4′-hydroxyflavone (10 mg/kg of body weight),4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate (Example 71) (10 mg/kg ofbody weight) and fenofibrate (100 mg/kg of body weight) were BIDadministered to hApoA-I transgenic mice daily for fourteen days by oralgavage in 0.5% Methylcellulose (w/v)/1% Tween 80 (w/v). Plasma wasassayed for ApoA-I (FIG. 3A), HDL cholesterol and total cholesterol(FIG. 3B) and percent weight gain (FIG. 3C).

In the hApoA-I transgenic mice, 4′-hydroxyflavone and4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate (Example 71) increased plasmaApoA-I with a net % change over vehicle of 32.44 and 12.82,respectively, after two weeks of treatment (FIG. 3A). Study grouptreated 4′-hydroxyflavone was selected for full lipoprotein cholesterolprofile analysis using NMR. Lipoprotein cholesterol profilesdemonstrated that treatment with 4′-hydroxyflavone resulted in a markedalteration in the distribution of cholesterol among lipoproteins (FIG.3B). In particular, 4′-hydroxyflavone caused a marked elevation in HDLcholesterol after two weeks of treatment (12.6% net % change). Notably,one adverse effect of fenofibrate treatment is liver weight gain,largely due to increased hepatic peroxisome proliferation. This wasconfirmed, as shown in FIG. 3C, that fenofibrate in male, day 15,hApoA-I transgenic mice caused a significant increase in liver weightgain when normalized to body weight, compared to vehicle.4′-hydroxyflavone and 4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate(Example 71) showed minor changes relative to vehicle. The lack ofchange in body weight in mice suggests that the compounds of theinvention may not act as peroxisomal proliferator activator receptoralpha ligands. These results indicate that the compounds of theinvention are useful for increasing plasma ApoA-I and elevatingcirculating HDL, without the adverse side effect associated with liverweight gain in a patient to whom the compound is administered.

Experiment B

4′-hydroxyflavone (3 mg/kg of body weight), 4′-hydroxyflavone (10 mg/kgof body weight), 4′-hydroxyflavone (30 mg/kg of body weight),2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (10 mg/kg of bodyweight), and fenofibrate (100 mg/kg of body weight) were BIDadministered to hApoA-I transgenic mice daily for fourteen days by oralgavage in 0.5% methylcellulose (w/v)/1% Tween 80 (w/v). In thisexperiment plasma was assayed for ApoA-I.

In the hApoA-I transgenic mice, 4′-hydroxyflavone at 10 mpk and2-(4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (Example 71) at 10 mpkincreased plasma ApoA-I with a net % change over vehicle 31.24 and 3.75,respectively, after two weeks of treatment. This trend is consistentwith results observed in Experiment A, that is 4′-hydroxyflavone and4-(4-oxo-4H-chromen-2-yl)phenyl nicotinate (Example 71) elevate thelevels of circulating ApoA-I protein in a mammalian system. A lack ofstatistically significant change in ApoA-I at 3 and 30 mpk over vehiclesuggests that the therapeutically effective amount of 4′-hydroxyflavonemay be between 3 and 30 mpk and, more preferably, 10 mpk to observe anincrease in ApoA-I.

Experiment C

In a number of different experiments following protocols similar toExperiments A and B, representative compounds of the invention andfenofibrate (positive control) were administered daily at various dosesto 7-8 week old hApoA-I transgenic mice for 14 days BID or SID by oralgavage in a dosing vehicle (Control 1 was 0.5% MC & 1% Tween 80 andControl 3 was F-101).

Table 6 below shows the effect of these compounds, and fenofibrate onthe percent change in plasma ApoA-I, relative to pretreatment values, inhApoA-I transgenic mice. All mice were treated BID for 14 days.

TABLE 6 In Vivo Effect on ApoA-I Expression Dose (mg/ Volume ApoA-ICompound kg) (ml/kg) N (% change) Control 1 0 5 8 11.942-(4-Hydroxy-phenyl)-pyrano[2,3- 3 5 8 18.87 b]pyridin-4-one (Example34) 2-(4-Hydroxy-phenyl)-pyrano[2,3- 10 5 8 36.64* b]pyridin-4-one(Example 34) 2-(4-Hydroxy-phenyl)-pyrano[2,3- 30 5 8 47.46*b]pyridin-4-one (Example 34) Control 1 0 5 4 3.422-(3-Fluoro-4-hydroxyphenyl) 10 5 8 14.45 pyrano[2,3-b]pyridine-4-one(Example 37) Fenofibrate 30 5 4 127.42* Control 3 0 5 4 (6.32)2-(4-Hydroxy-phenyl)-1H-quinolin- 10 5 8 32.81* 4-one (Example 51)2-(4-Hydroxy-phenyl)-pyrano[2,3- 10 5 8 30.94* b]pyridin-4-one (Example34) 2-(4-Hydroxy-phenyl)-pyrano[3,2- 10 5 8 (0.97) b]pyridin-4-one(Example 35) 2-(5-Hydroxy-pyridin-2-yl)- 10 5 8 5.62 chromen-4-one(Example 46) 2-Pyridin-4-yl-chromen-4-one 10 5 8 22.73* (Example 47)Fenofibrate 30 5 3 74.40* Control 3 0 5 4 1.11 3-(4-Hydroxyphenyl)-2H-10 5 8 13.22 isoquinolin-1-one (Example 53) 2-(6-Hydroxypyridin-3-yl)-10 5 8 4.94 chromen-4-one (Example 48) 2-(4-Hydroxyphenyl)pyrano[2,3- 105 8 17.01 c]pyridin-4-one (Example 36) 2-(4-Hydroxyphenyl)-4H- 10 811.20 pyrano[3,2-c]pyridine-4-one (Example 39)4-(1,6-Naphthyridin-7-yl)phenol 10 5 8 9.49 (Example 57) Fenofibrate 305 4 68.94* *p < 0.05

These results demonstrate that compounds of the invention activate thehuman ApoA-I transgene in mice, leading to an increase in circulatingApoA-I. Thus, the compounds of the invention and pharmaceuticallyacceptable salt or hydrate thereof, can be expected to elevate ApoA-Iprotein level and to be useful for elevating plasma ApoA-I levels in apatient to whom the compounds are administered.

Example 94 Measurement of AGCCCCCGC Sequence Element Induction

Caco-2 or HepG2 cells are exposed to effective concentrations ofcompounds of the invention. The cells are first transfected usingstandard techniques with a reporter construct comprising one or morecopies of the nine nucleotides, 5′-AGCCCCCGC-3′ acting as an enhancerelement (Kilbourne et al., J. Biol. Chem. 270:7004 (1995)), operablylinked to a promoter (for example, the thymidine kinase (TK) promoter),operably linked to a reporter gene (for example luciferase, CAT, or theApoA-I gene) along with pRSV-β-galactosidase, which monitorstransfection efficiency (as taught in Wong). Compounds of the inventionare then dissolved in appropriate solvent (for example, DMSO) and thenadded to the culture media for 16 hours. At the end of the treatment,the cells are harvested, and the reporter gene activity is measuredusing standard assays. Increased or decreased reporter gene activityindicates that compounds of the invention have the ability to modulatetranscription from promoters that contain the nine nucleotide sequence5′-AGCCCCCGC-3′, which is believed to comprise an egr-1 responsiveelement.

Example 95 Measurement of Antioxidant Effectiveness

The antioxidant performance of compounds of the invention isdemonstrated by measuring the extent of low density lipoproteinhydroxyperoxide by copper catalyzed autoxidation using a published dyebased color assay. FOX Assay, Zadeh, Methods in Enzymology, 300:58(1999). Samples containing only LDL and copper sulfate without testmaterials, serve as a positive control for comparison with identicalmixtures containing test materials.

Human Low Density Lipoprotein (Sigma Chemical Company L2139) inphosphate buffered saline pH 7.4 is mixed with copper sulfate.Incubation with effective amounts of compounds of the invention at 25°C. or 37° C. open to air effects oxidation, and the mixture is sampledat time zero and between 3 and 20 hours of incubation for measurement ofhydroperoxide in the FOX assay. Samples are read in a microtitre platereader. Decreased hydroperoxide as measured by the FOX assay reveals theanti-oxidant activity of compounds of the invention and their usefulnessfor the treatment or prevention of disorders, diseases or conditionsassociated with oxidation or benefiting from the administration ofanti-oxidants. An example of such a condition that would benefit fromthe treatment of anti-oxidants is cardiovascular disease.

Example 96 Measurement of Antioxidant Activity by LDL Oxidation Assay

The method of Esterbauer (Esterbauer, H. et al Free Radic Res Commun6:67 (1989)) may be used, with some modification as follows: thecompound is dissolved with an appropriate solubilizing agent in aphosphate buffer solution (PBS, 0.15 M NaCl-0.05 M Na PhosphateBuffer-pH 7.4). The exact concentration is noted (approximately 30-60μL/mL of extract to be measured). To 100 μL of this solution is added to900 μL of an oxidizing buffer (made from human LDL, 120 μL of 5 mg/mLsolution with d=1.019-1.063 g/mL, purchased from PerImmune, Rockville,Md.) and copper sulfate (20 μL of 10 mM aqueous solution) in 8 mL PBS).A blank sample made with 100 μL PBS and 900 μL oxidizing buffer is alsoprepared. Each solution is then transferred to a 1 cm quartz cuvette,and the cuvette is placed into thermostat (37° C.). An HP-8452A DiodeArray Spectrophotometer measures optical density at 234 nm (OD sub 234),making a measurement every 5 minutes. The lag time for oxidation iscalculated as the maximum of the first derivative of the optical densitycurve. A standard containing ascorbic acid is run with each assay.

Example 97 Effects on LDL-Cholesterol, HDL-Cholesterol and TriglycerideLevels in Male Sprague-Dawley Rats

Compounds of the invention are administered daily at a dose of 100 mg/kgto chow fed male Sprague-Dawley rats for seven days in the morning byoral gavage in 1.5% carboxymethylcellulose/0.2% Tween-20 (dosingvehicle). Animals are weighed daily. Animals are allowed free access torodent chow and water throughout the study. After the seventh dose,animals are sacrificed in the evening and blood serum is assayed forlipoprotein cholesterol profiles, serum triglycerides, total cholesterolVLDL, LDL, and HDL cholesterol, and the ratio of HDL cholesterol to thatof VLDL plus LDL cholesterol, apolipoproteins AI, C-II, C-III, and E byimmunoelectrophoresis, and percent weight gain.

Blood serum is assayed for total cholesterol and triglycerides,lipoprotein cholesterol profiles, VLDL plus LDL cholesterol combined(also referred to as ApoB containing lipoprotein cholesterol or non-HDLcholesterol), HDL cholesterol, and the ratio of HDL cholesterol to thatof VLDL plus LDL cholesterol, serum glucose, and non-esterified fattyacids, and percent weight gain.

Example 98 Effects on LDL-Cholesterol, HDL-Cholesterol and TriglycerideLevels in Obese Female Zucker Rats

Compounds of the invention and troglitazone are administered daily atvarious doses to 10-week old chow fed obese female Zucker rats for 14days in the morning by oral gavage in 1.5% carboxymethylcellulose/0.2%Tween-20 (dosing vehicle). Animals are weighed daily. Animals areallowed free access to rodent chow and water throughout the study. Bloodglucose is determined after a 6-hour fast in the afternoon withoutanesthesia from a tail vein. Serum is also prepared from a blood samplesubsequently obtained from the orbital venous plexus (with O₂/CO₂anesthesia) prior to and after one week treatment and used lipid andinsulin determinations. At two weeks, blood glucose is again determinedafter a 6-hour fast without anesthesia from a tail vein. Soonthereafter, animals are sacrificed by CO₂ inhalation in the evening andcardiac blood serum is collected and assessed for various lipids andinsulin. Body weight is determined daily prior to dosing and at the timeof euthanasia.

Blood serum is assayed for serum non-HDL cholesterol, HDL-cholesterol,triglyceride and body weight (relative to pretreatment values) in fasted(6 hours) chow-fed obese female Zucker rats. Blood glucose and seruminsulin levels are determined from fasted rats just prior to andfollowing one and two weeks of treatment. Blood glucose is maintained atslightly elevated levels for 10-12 week old obese Zucker rats duringtreatment with all doses, with the exception of the doses, whereby thecompounds show a tendency to lower blood glucose. Percent liver to bodyweight is determined after two weeks of treatment at the time ofsacrifice.

Example 99 Effects on Lipoprotein Cholesterol Profile in LDLReceptor-Deficient Mice

Homozygous familial hypercholesterolemia is a rare human disease(affecting about 1/1,000,000) characterized by absent or defective LDLreceptors, markedly elevated serum LDL cholesterol levels and very earlyand severe onset of atherosclerosis. The more common form of thisdisease in humans, heterozygous familial hypercholesterolemia, occurs inabout one in every 500 humans. Patients with the heterozygous form ofthis disease also present with elevated LDL levels and early onset ofatherosclerosis.

The effect of the compounds of the invention on LDL levels in a murinemodel of homozygous familial hypercholesterolemia (Ishibashi et al., J.Clin. Invest. 92:883 (1993); Ishibashi et al., J. Clin. Invest. 93:1885(1994)) is studied. LDL receptor-deficient mice have elevated LDLcholesterol relative to wild type mice when fed a chow diet. When fedcholesterol-enriched diets, these mice develop atherosclerosis.

Example 100 Effect on Synthesis of Non-Saponified and Saponified Lipidsin Hepatocytes Isolated from Male Sprague-Dawley Rats

A male Sprague-Dawley rat is anesthetized by administration of sodiumpentobarbitol by intraparitoneal injection at 50 mg/kg. In situperfusion of the liver is performed as follows. The abdomen of theanimal was opened, the portal vein cannulated, and the liver perfusedwith WOSH solution (149 mM NaCl, 9.2 mM Na HEPES, 1.7 mM fructose, 0.5mM EGTA, 0.029 mM phenol red, 10 U/ml heparin, pH 7.5) at a flow rate of30 ml/min for 6 minutes. To digest the liver, DSC solution (6.7 mM KCl,143 mM NaCl, 9.2 mM Na HEPES, 5 mM CaCl₂-2H₂O, 1.7 mM fructose, 0.029 mMPhenol red, 0.2% BSA, 100 U/ml collagenase Type I, 93 U/mlhyaluronidase, 160 BAEE/ml trypsin inhibitor, pH 7.5) is perfusedthrough the liver at a flow rate of 30 ml/min for 6 minutes at atemperature of 37° C. After digestion, cells are dispersed in a solutionof DMEM containing 2 mM GlutMax-1, 0.2% BSA, 5% FBS, 12 nM insulin, 1.2μM hydrocortisone to stop the digestion process. The crude cellsuspension is filtered through three layers of stainless steel mesh withpore sizes of 250, 106, and 75 μm respectively. Filtered cells arecentrifuged at 50×g for two minutes and the supernatant discarded. Theresulting cell pellet is resuspended in DMEM and centrifuged again. Thisfinal cell pellet is resuspended in DMEM+HS solution (DMEM containing 2mM GlutMax-1, 20 nM delta-aminolevulinic acid, 17.4 mM MEM non-essentialamino acids, 20% FBS, 12 nM insulin, 1.2 μM hydrocortisone) and platedto form monolayer cultures at a density of 100×10³ cells/cm² on collagencoated culture dishes. Four hours after initial plating, media ischanged to DMEM+ (DMEM containing 2 mM GlutMax-1, 20 nMdelta-aminolevulinic acid, 17.4 mM MEM non-essential amino acids, 10%FBS, 12 nM insulin, 1.2 μM hydrocortisone) and remained on cellsovernight.

To test the effect of compounds of the invention on synthesis rates ofnon-saponified and saponified lipids, the monolayer cultures are exposedto 1 μM of lovastatin or 100 μM of test compound in DMEM+ containing 1μCi/ml ¹⁴C-acetate. Control cells are exposed to the same media lackinglovastatin or the test compounds. All are exposed to 0.1% DMSO.Metabolic labeling with ¹⁴C-acetate continued for 2 hr at 37° C. Afterlabeling, cells are washed twice with 1 ml of PBS followed by lysing in1 ml of deionized water. Cells are scraped from the dishes, transferredto glass tubes and sonicated. 2.5 ml of 2:1 chloroform/methanol mixturewas added followed by 1.5 ml of Phosphate Buffered Saline (PBS). Tocorrect for extraction efficiency in the upcoming extractions, 3000 dpmof ³H-cholesterol was added to each tube. Tubes are shaken for 30 min.to extract lipids into the organic phase followed by centrifugation for10 minutes at 1000×g to separate the organic and aqueous phases. Thelower organic phase containing total lipids is removed and placed in anew tube. The organic solution is evaporated under N₂. The dry lipidextract was resuspended in 1 ml of 93% ethanol containing 1 M KOH andplaced at 70° C. for 2.5 hours. After the reaction and cooling, 2 ml ofhexane and 2.5 ml of water is added to each tube followed by rigorousshaking for 10 min. Tubes are centrifuged for 10 min. at 1000×g and theorganic (top) layer containing the non-saponified lipids is transferredto a new tube followed by evaporation of the organic solvent under N₂.The aqueous phase containing the saponified lipids is also transferredto a new tube. The non-saponified lipid extract, after drying, isresuspended in toluene and an aliquot of the suspension is added to ascintillation cocktail for radioactive counting. The number of ¹⁴Ccounts representing the incorporation of ¹⁴C-acetate into non-saponifiedlipids is corrected for extraction efficiency, based on the recovery of³H counts extracted. To isolate saponified lipids, 1.5 ml of aqueousphase solution is mixed with 400 μl of 1 M HCl, and then lipids areextracted by the addition of 2.5 ml of 2:1 chloroform:methanol, 1.5 mlof PBS, and 1 ml of water followed by rigorous shaking and isolation ofthe organic phase. The organic phase from this extraction is evaporatedunder N₂ and resuspended in toluene. Its radioactivity is counted usingscintillant to provide the rate of ¹⁴C-acetate incorporation intosaponified lipid.

Example 101 Measurement and Comparison of HDL, LDL, VLDL andTriglyceride Levels in Humans

Compounds of the invention are administered daily to human subjects.Other dietary uptake is monitored and held constant between individuals.Blood samples are taken on the day 0, prior to commencing theadministration of the compounds, and once weekly for 3 to 6 months.Blood serum is assayed for total cholesterol and triglycerides,lipoprotein cholesterol profiles, VLDL plus LDL cholesterol combined(also referred to as ApoB containing lipoprotein cholesterol or non-HDLcholesterol), HDL cholesterol, HDL₂ and HDL₃ cholesterol fractions, andthe ratio of HDL cholesterol to that of VLDL plus LDL cholesterol,utilizing standard, commercially available cholesterol tests, such asthe VAP test (Atherotech Inc, Birmingham, Ala.) which can reproduciblymeasure these parameters from a small sample of human blood.Alternatively, HDL₂ and HDL₃ can be measured from blood by the method ofKulkarni et al., J. Lipid Res. 38:2353 (1997) or by the method of Gidezet al., J. Lipid Res. 23:1206 (1982). Compounds of the invention whichincrease total HDL, increase HDL₂, decrease total LDL, decrease VLDL,decrease triglyceride, or increase the HDL/total cholesterol or HDL/LDLratios as determined in such a blood test are useful for the treatmentof cholesterol or lipid associated disorders.

Example 102 Measurement of Atherosclerotic Lesion Size UsingProteoglycan-Binding-Defective LDL

A nucleic acid construct may be used to generate mice expressing aproteoglycan-binding-defective LDL. The transgenic mice are fed a dietcontaining 1.2% cholesterol, 0.5% bile salts, and 20% fat for 17 weeks.The mice are then sacrificed, and the aortas are perfusion fixed andanalyzed with the en face procedure, in which the entire aorta is pinnedout flat, stained with Sudan IV, and analyzed with a morphometricimage-analysis system (Image-1/AT) to quantitate the extent ofatherosclerosis.

Example 103 Determination of ACAT Inhibition

The activity of compounds of the invention as inhibitors of ACAT may bedetermined by known methods, for example, those taught in U.S. Pat. No.6,165,984, incorporated herein by reference and summarized below.

First, rats are sacrificed by decapitation and the livers excised. 1 gof each of the livers is homogenized in 5 ml of homogenization medium(0.1 M KH₂PO₄, pH 7.4, 0.1 mM EDTA and 10 mM β-mercaptoethanol). Thehomogenate is centrifuged at 3,000×g for 10 min. at 4° C. and thesupernatant thus obtained is centrifuged at 15,000×g for 15 min. at 4°C. to obtain a supernatant. The supernatant is put into anultracentrifuge tube (Beckman) and centrifuged at 100,000×g for 1 hourat 4° C. to obtain microsomal pellets, which are then suspended in 3 mlof the homogenization medium and centrifuged at 100,000×g for 1 hour at4° C. The pellets thus obtained are suspended in 1 ml of thehomogenization medium. The concentration of proteins in the resultingsuspension is determined by Lowry's method and then adjusted to 4 to 8mg/ml. The resulting suspension is stored in a deep freezer (Biofreezer,Form a Scientific Inc.).

6.67 μl of 1 mg/ml cholesterol solution in acetone is mixed with 6 μl of10% Triton WR-1339 (Sigma Co.) in acetone and, then, acetone is removedfrom the mixture by evaporation using nitrogen gas. Distilled water isadded to the resulting mixture in an amount to adjust the concentrationof cholesterol to 30 mg/ml. To 10 μl of the resulting aqueouscholesterol solution is added 10 μl of 1 M KH₂ PO₄ (pH 7.4), 5 μl of 0.6mM bovine serum albumin (BSA), 10 μl of microsome solution obtained in(Step 1) and 55 μl of distilled water (total 90 μl). The mixture ispre-incubated in a waterbath at 37° C. for 30 min.

10 μl of (1-¹⁴C) oleoyl-CoA solution (0.05 μCi, final concentration: 10μM) is added to the pre-incubated mixture and the resulting mixture isincubated in a waterbath at 37° C. for 30 min. To the mixture is added500 μl of isopropanol:heptane mixture (4:1(v/v)) 300 μl of heptane and200 μl of 0.1 M KH₂PO₄ (pH 7.4), and the mixture is mixed violently byusing a vortex and then allowed to stand at a room temperature for 2min. 200 μl of the resulting supernatant is put in a scintillationbottle and 4 ml of scintillation fluid (Lumac) is added thereto. Themixture is assayed for radioactivity with liquid scintillation counter.ACAT activity is calculated as picomoles of cholesteryl oleatesynthesized per min. per mg protein (pmoles/min/mg protein).

Example 104 Determination of Inhibition of HMG-CoA Reductase

The potency of inhibition of HMG-CoA reductase by compounds of theinvention may be determined using known methods, such as that taught inU.S. Pat. No. 5,877,208, incorporated herein by reference and summarizedbelow.

Rats are sacrificed by decapitation and the livers are excised andimmediately placed in an ice-cold homogenization medium (50 mM KH₂ PO₄(pH 7.0), 0.2M sucrose, 2 mM dithiothreitol (DTT). The livers arehomogenized in the homogenization medium (2 ml medium/g of the liver)with a Waring blender for 15 sec. (three strokes with a motor-drivenTeflon pestle in a Potter-Elvehjem type glass homogenizer). Thehomogenate is centrifuged at 15,000×g for 10 min. and the supernatantthus obtained is centrifuged at 100,000×g for 75 min. to obtainmicrosomal pellets, which are then resuspended in the homogenizationmedium containing 50 mM EDTA and centrifuged at 100,000×g for 60 min.The supernatant containing the microsome is used as an enzyme source.

The activity of HMG-CoA reductase is determined by employingradiolabeled ¹⁴C HMG-CoA, in accordance with the method of Shapiro etal. (Shapiro et al Biochemica et Biophysica Acta 370:369 (1974)) asfollows. The enzyme in the supernatant containing the microsome obtainedin (Step 1) is activated at 37° C. for 30 min. Added to a reaction tubeis 20 μl of HMG-CoA reductase assay buffer (0.25M KH₂ PO₄ (pH 7.0), 8.75mM EDTA, 25 mM DTT, 0.45M KCl and 0.25 mg/ml BSA), 5 μl of 50 mM NADPH,5 μl of radiolabeled ¹⁴C HMG-CoA (0.05 μCi/tube, final conc. 120 μM),and 10 μl of activated microsomal enzyme (0.03-0.04 mg), and the mixtureis incubated at 37° C. for 30 min. The reaction is terminated by adding10 μl of 6M HCl to the mixture, and the mixture is incubated at 37° C.for 15 min. to allow complete lactonization of the product. Theprecipitate is removed by centrifugation at 10,000×g for 1 min. and thesupernatant is applied to a Silica gel 60G TLC plate (Altech, Inc.,Newark, U.S.A.) and then developed with benzene:acetone (1:1, v/v). Theappropriate region is removed by scraping with a disposable cover slipsand assayed for radioactivity with 1450 Microbeta liquid scintillationcounter (Wallacoy, Finland). Enzyme activities are calculated aspicomoles mevalonic acid synthesized per min. per mg protein(pmoles/min/mg protein). Control rats show a relatively high HMG-CoAreductase activity, while the HMG-CoA activities observed with rats fedcompounds of the invention are lower than that of the control group.

Example 105 Method of Determining the ABCA-1 Activating Ability

This test will demonstrate the effectiveness of compounds of theinvention on ABCA-1 gene expression, using a known method, as taught inU.S. Pat. No. 6,548,548, incorporated herein by reference. Briefly, thepGL3 luciferase reporter vector system (Promega, Madison, Wis.) is usedto create a recombinant plasmid to measure reporter gene expressionunder control of the ABCA-1 promoter.

Plasmid pGL3-Basic (Promega, Madison, Wis.; Cat. #E1751) is used as acontrol plasmid containing the promoterless luciferase gene. Thereporter construct containing the ABCA-1 promoter and luciferase gene ismade by cloning a genomic fragment from the 5′ flanking region of theABCA-1 gene (hAPR1 5′ promoter, corresponding to nucleotides 1080-1643of SEQ ID NO: 3 as disclosed in U.S. Pat. No. 6,548,548) into the SacIsite of the GL3-Basic plasmid to generate plasmid GL-6a. Next, plasmidGL-6a is digested with SpeI and Acc65I. A BsiWI-SpeI fragment excisedfrom a lambda subclone, representing the ABCA-1 genomic sequencecorresponding to nucleotides 1-1534 of SEQ ID NO: 3 is ligated into theremaining vector/ABCA-1 promoter fragment produced by this digestion.The resultant plasmid, pAPR1, encodes the luciferase reporter gene undertranscriptional control of 1.75 kb of the human ABCA-1 promotersequence.

The control or pAPR1 plasmid wisas transfected into confluent culturesof RAW 264.7 cells maintained in DMEM containing 10% fetal bovine serum.Each well of a 12 well dish is transfected for 5 hours with eitherpGL3-Basic, pGL3-Promoter or pAPR1 DNA (1 μg), luciferase plasmid DNA (1μg), and 12 μl of Geneporter reagent (Gene Therapy Systems, San Diego,Calif.; Cat. #T201007). In addition, 0.1 μg of pCMVβ plasmid DNA(Clontech, Palo Alto, Calif., Cat. #6177-1) is added as a control fortransfection efficiency. After 5 hours, the culture medium is replacedwith serum-free DMEM/BSA in the presence or absence of acetylated LDL(100 μg/ml) and incubated for 24 hours.

Following transfection, the cells in each well are lysed in 70 μl of 1×cell lysis reagent (Promega, Madison, Wis., Cat. #E3971), subjected toone freeze-thaw cycle, and the lysate cleared by centrifugation for 5minutes at 12,000×g. After centrifugation, 100 μl of luciferase assayreagent (Promega, Madison, Wis.; Cat. #E1501) is added to 10 μl oflysate. The luciferase activity of each lysate is measured as lightunits using a luminometer. Additionally, the β-galactosidase activity ofeach lysate is measured using the chemiluminescent assay reagentssupplied in the Galacto-light kit according to the manufacturer'sinstructions (Tropix Inc., Bedford, Mass.: Cat. #BL100G). The normalizedluciferase activity for each lysate is determined by dividing theluciferase activity value by the determined β-galactosidase value andreported as relative light units.

Example 106 Measurement of Reduced Hypertension In Vivo

A pressure transducer is connected to the right carotid artery via acatheter containing heparinized saline. The mean arterial pressure andheart rate are recorded. The rats are anesthetized with nembutal at aninitial dose of 35 mg/kg body weight with additional smaller injectionsas necessary. The compounds are dissolved in a pharmaceutical carrier(such as Abbott's 5% dextrose USP) and injected into the rats via acatheter in the right femoral vein. Positive controls that may beemployed include sodium nitroprusside and NaNO₂, while NaNO₃ may beemployed as a negative control. The results will show that the compoundsprovided for in the invention are potent anti-hypertensives, thatdecreases blood pressure significantly. The peak value of the bloodpressure decrease should take a short time to reach, for example,approximately one minute, after injection and the blood pressure shouldstart to rise again soon thereafter and should have totally recoveredwithin about approximately 10 to 15 minutes.

Example 107 Measurement of the Reduction of Degree of Restenosis AfterArterial Injury in High Cholesteric Rabbits

The procedure of Tomaru, as described in U.S. Pat. No. 5,595,974 andfurther described by Goodman in U.S. Pat. No. 6,022,901, both hereinincorporated by reference, may be used to evaluate the utility of thecompounds of the invention to preventing restenosis in high cholestericrabbits.

Example 108 Use in Preventing Restenosis in Humans

The procedure of Tardif et al., New England J. Med. 337:365 (1997)) maybe carried out as described by Goodman in U.S. Pat. No. 6,022,901,incorporated herein by reference, to examine the ability of compounds ofthe invention to prevent restenosis in humans.

Example 109 Measurement of Platelet Anti-Aggregating Activity

Platelet anti-aggregating activity may be evaluated in vitro on humanplatelets stimulated by thrombin in accordance with the method describedby Bertele et al., Science 220:517 (1983).

Example 110 Measurement of the Influence on ADP-Induced Aggregation ofPlatelets in Rabbits

Aggregation of platelet testing: Rabbit blood is sampled by cardiacpuncture from rabbit with silicon-coated syringe. The blood is mixedwith 3.8% sodium citrate at 9:1 and spun at 1,000 rpm for 6 minutes. 1ml of the platelet-rich plasma is transferred to a silicon-coated 2 mlcell, mixed and read for transmittance (Ti), with a spectrophotometer.0.02 ml of ADP (10 mu.M) is added, stirred, and read for transmittanceof the platelet-containing-plasma once per minute and the maximaltransmittance (Tm) is obtained within 10 minutes. Spin the blood sampleat 3000 rpm for 45 minutes and read for transmittance.

Example 111 Measurement of the Effect on Collagen InducedThrombo-Cytopenia In Vivo

Male rats (Charles River, CRL:CD(SD), 400-450×g) are anesthetized withSodium pentabarbital (65 mg/kg, Vet Labs, Limited, Inc., Lenexa, Kans.).Two incisions are made to expose both jugular veins. Using an infusionpump (Harvard Apparatus, South Natick, Mass.) and a 5 cc syringe with a19 gauge butterfly, the test compound or vehicle is infused into theleft jugular vein at a rate of 0.39 ml/min for 3 minutes. After 2minutes of compound/vehicle infusion, collagen (60 μg/kg) (HelenaLaboratories, Beaumont, Tex.) is injected with a 1 ml syringe into theright jugular vein. The body cavity is opened and the vena cava isexposed for blood sampling. One minute after the collagen injection,compound infusion is stopped and blood is sampled from the vena cava(within 30 sec) with a 3 cc syringe containing 0.3 mg of 4.5% EDTA/Tris(0.1M) (pH 7.35) plus 150 μM indomethacin. Platelet rich plasma (PRP) isprepared by centrifuging the blood at 126×g for 10 min. 5 μl of PRP iscounted in 20 ml of Isoton.® III in a Coulter Counter. Percentinhibition of collagen induced aggregation is calculated by comparisonof the number of platelets counted in treated animals with numbers foranimals receiving no collagen and with counts from animals receivingvehicle and collagen. Estimation of potency is based on inhibition ofcollagen-induced thrombocytopenia.

Example 112 Measurement of In Vivo Anti-Psoriatic Effectiveness

A topical formulation comprising a compound of the invention isadministered to the affected area of human patients suffering frompsoriasis. A control formulation, containing none of the compound of theinvention, is applied to a comparable area of the patient. Theeffectiveness of the compound is determined by analyzing the improvementin inflammation and decrease in proliferative cells at the site at whichthe compound is applied compared to the site at which controlformulation is applied at 3 and 7 days following administration.

Example 113 Measurement of Protein Kinase Inhibition

A compound of the invention is mixed with radio-labeled ATP, anappropriate protein kinase and an appropriate substrate in anappropriate buffer. Following incubation the reaction is stopped byspotting onto filter paper and a scintillation counter employed toquantify the difference in ATP addition to the substrate, which measuresthe amount of protein kinase inhibition, when compared to control.

Example 114 Measurement of Inhibition of Neutrophil Activation

A compound of the invention is tested using the protocol of Tudan,Biochem. Pharmacol. 58:1869 (1999). This test demonstrates the abilityof the test compound to inhibit the activation of neutrophils caused bycrystals and by chemoattractants such as fMLP.

Example 115 Measurement of Inhibition of TPA-Induced Inflammation

A compound of the invention is tested by a modified method of Marks etal., Cancer Res. 36:2636 (1976) to demonstrate the compound'seffectiveness against inflammation induced by application of12-O-tetradecanoylphorbol-13-acetate (TPA). The compound is applied toan ear of a mouse, followed by application of TPA. Four hours later abiopsy punch of the mouse ear is weighed to measure edema, compared to abiopsy punch of the other ear which received no compound.

Example 116 Measurement of the Inhibition of Carrageenan-InducedInflammation

A compound of the invention is tested by the method of Slowing et al., JWrhnoph Exol. 43:9 (1994) in Wistar rats. Animals receive intradermalinjections of Freund's adjuvant into the tail. Seven days later, thetest compound is administered, followed one hour later by a suspensionof carrageenan in saline solution into the left hind paw. Paw volume ismeasured by water plethysmography and compared to control.

Example 117 Measurement of Cancer Chemopreventative Activity

C3H/10T1/2 clone 8 cells (ATCC) are treated with a compound of theinvention by the method of Mondal et al., Cancer Res. 36:2254 (1976).The cells in culture are treated with 3-methylcholanthrene for 24 hours,followed by washing a five days of incubation in fresh medium. TPA issubsequently added to the medium, with or without the test compound.Seven weeks after confluency is reached, fixation with methanol andstaining with Giemsa reveals Type II and III transformed foci, which arescored to demonstrate effectiveness of inhibition of two-stagetransformation by the test compound.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1. A compound of Formula I:

wherein X is O; Y is CO; R₁, R₃, R₄, R₅, R₆, R₈, and R₉ are eachindependently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl,amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide and thioketone; R₂ is selected fromalkoxy, aryloxy, alkenyl, alkynyl, amide, amino, aryl, arylalkyl,carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen,haloalkyl, heteroaryl, heterocyclyl, hydrogen, ketone, nitro, phosphate,sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone;R₇ is selected from aryloxy, alkyl, alkenyl, alkynyl, amide, aryl,arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro,phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide andthioketone; R₁₀ is selected from aryloxy, alkenyl, alkyl, alkynyl,amide, amino, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, ketone,nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid,sulfonamide and thioketone; each W is independently selected from C andN, wherein if W is N, then p is 0 and if W is C, then p is 1; at leastone W is N; Z₁ and Z₃ are each a single bond; and Z₂ is a double bond;and pharmaceutically acceptable salts thereof.
 2. A compound of FormulaVII:

wherein: R₁, R₂, R₃, R₅, R₆, R₃, R₉, and R₁₀ are each independentlyselected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino,aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether,formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen,hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl,sulfonic acid, sulfonamide and thioketone; R₇ is selected from aryloxy,alkyl, alkenyl, alkynyl, amide, aryl, arylalkyl, carbamate, carboxy,cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl,sulfonyl, sulfonic acid, sulfonamide and thioketone, or two adjacentsubstituents selected from R₁, R₂, R₃, R₅, R₆, R₇, R₈, R₉, and R₁₀ areconnected in a 5 or 6-membered ring to form a bicyclic aryl or bicyclicheteroaryl; and pharmaceutically acceptable salts thereof.
 3. A compoundthat is 2-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1, where R₇ is hydroxyl.
 5. A compound according to claim 1,wherein at least one W in the A ring is N.
 6. A compound according toclaim 1, wherein R₅, R₆, R₈, R₉ and R₁₀ are each hydrogen.
 7. A compoundaccording to claim 1, wherein at least one W in the B ring is N.
 8. Acompound according to claim 1, wherein the W in the C ring is selectedfrom N and NR₁₀, where R₁₀ is hydrogen or methyl.
 9. A compoundaccording to claim 1, wherein R₈ is halogen.
 10. A compound according toclaim 1, wherein at least one of R₁, R₂, R₃ and R₄ is alkoxy.
 11. Acompound selected from 2-(5-Methoxy-pyridin-2-yl)-chromen-4-one;2-(5-Hydroxy-pyridin-2-yl)-chromen-4-one;2-(6-Hydroxy-pyridin-3-yl)-chromen-4-one;5,7-Dimethoxy-2-(4′-hydroxy-phenyl)-quinolin-4-one;5,7-Dihydroxy-2-(4-hydroxy-phenyl)-quinolin-4-one;2-(4-Hydroxy-phenyl)-pyrano[3,2-b]pyridin-4-one;2-(4-Methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(4-Hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one;2-(4-(2-Hydroxyethoxy)phenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(3-Fluoro-4-hydroxyphenyl)pyrano[2,3-b]pyridine-4-one;2-(4-Hydroxy-3-methylphenyl)-4H-pyrano[2,3-b]pyridine-4-one;4-(4-Oxo-4H-pyrano[2,3-b]pyridine-2-yl)benzonitrile;2-(3-Chloro-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one;2-(3-Bromo-4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one;2-(4-Hydroxy-3-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one; 2-(4-Hydroxy-phenyl)-pyrano[2,3-c]pyridin-4-one;2-(4-hydroxy-phenyl)-pyrano[3,2-c]pyridin-4-one;3-(4-Hydroxyphenyl)-2H-isoquinolin-1-one;3-(3-Fluoro-4-hydroxyphenyl)-5-methoxyisoquinolin-1(2H)-one;2-Fluoro-4-(5-methoxy-1-(methylamino)-isoquinolin-3-yl)phenol;6-Naphthalen-2-yl-pyridin-3-ol; 4-Isoquinolin-3-yl-phenol;4-(1,6-Naphthyridin-7-yl)phenol;2-(4-Hydroxy-phenyl)-[1,4]naphthoquinone;2-(4-Hydroxyphenyl)benzo[e][1,3]oxazin-4-one;6-Naphthalen-2-yl-pyridin-3-ol;2-(4-Ethoxycarbonyloxy-phenyl)-4-oxo-4H-quinoline-1-carboxylic acidethyl ester; 4-(4-oxo-4H-pyrano[2,3-b]pyridine-2-yl)phenyl acetate;4-(Isoquinolin-3-yl)phenyl 2-amino-5-guanidinopentanoate;4-(1-Oxo-1,2-dihydroisoquinolin-3-yl)phenyl2-amino-5-guanidinopentanoate;5,7-Difluoro-2-(4-hydroxy-phenyl)-chromen-4-one;2-(3,5-Difluoro-4-hydroxyphenyl)chromen-4-one;2-(4-Hydroxy-3,5-dimethylphenyl)chromen-4-one;2-(4-Methoxy-phenyl)-thiochromen-4-one;2-(4-Hydroxy-phenyl)-thiochromen-4-one;2-(4-Hydroxyphenyl)-3-methyl-4H-chromen-4-one;4-(6-Bromo-4-oxo-4H-chromen-2-yl)-2-fluorophenyl acetate;1-(2-Nitro-4-methoxy-phenyl)-chromen-4-one;2-(4-Hydroxy-2-nitrophenyl)chromen-4-one;2-(2-Amino-4-methoxy-phenyl)-chromen-4-one;2-(2-Amino-4-hydroxy-phenyl)-chromen-4-one;N-[5-Hydroxy-2-(4-oxo-4H-chromen-2-yl)-phenyl]acetamide;6-Hydroxy-2-(4-hydroxymethylphenyl)chromen-4-one;2-(2-Fluoro-4-hydroxyphenyl)chromen-4-one;2-(4-Hydroxyphenyl)-8-nitro-4H-chromen-4-one;2-(4-Hydroxyphenyl)-8-methoxy-4H-chromen-4-one;2-(4-Hydroxyphenyl)-5,7-dimethoxy-4H-chromen-4-one;2-(3-Bromo-4-hydroxyphenyl)-4H-chromen-4-one;2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-carbonitrile;2-(4-Methoxy-phenyl)-chromen-4-one;2-(3-Fluoro-4-hydroxyphenyl)chromen-4-one;2-(4-Hydroxyphenyl)-4-oxo-4H-chromene-6-sulfonic acid;6-Hydroxymethyl-2-(4-hydroxyphenyl)chromen-4-one;6-((Dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one;8-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;2-(4-Hydroxy-phenyl)-chromen-4-one;7-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;5-Hydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;5,7-Dihydroxy-2-(4-hydroxy-phenyl)-chromen-4-one;5,7-Dihydroxy-2-phenyl-chromen-4-one; 5-Hydroxy-2-phenyl-chromen-4-one;2-(4-Acetoxy-phenyl)-thiochromen-4-one;2-(4-Acetoxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one;2-(4-Hydroxy-phenyl)-1,1-dioxo-1H-1λ⁶-thiochromen-4-one;2-(2-(4-Hydroxyphenyl)-4-oxo-4H-chromen-3-yl)acetonitrile;3-(Hydroxymethyl)-2-(4-hydroxyphenyl)-4H-chromen-4-one;2-(4-Hydroxyphenyl)-3-(methoxymethyl)-4H-chromen-4-one;4-Naphthalen-2-yl-phenol; 3-(4-Hydroxyphenyl)-naphthalene-1-ol;4-(Benzo[b][1,4]dioxin-2-yl)phenyl acetate;4-(Benzo[b][1,4]dioxin-2-yl)phenol; 4-(4H-Chromen-2-yl)-phenol;Nicotinic acid 4-(4-oxo-4H-chromen-2-yl)-phenyl ester; Acetic acid4-(4-oxo-4H-chromen-2-yl)-phenyl ester; 2-Amino-5-guanidino-pentanoicacid 4-(4-oxo-4H-chromen-2-yl)phenyl ester; and2-(4-(Nicotinoyloxy)phenyl)-4-oxo-4H-chromene-5,7-diyl dinicotinate, andpharmaceutically acceptable salts thereof.
 12. A pharmaceuticalcomposition comprising a compound according to claim 1, 2, or 11, and apharmaceutically acceptable carrier.